The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.743G>A (p.Arg248Gln)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.743G>A (p.Arg248Gln)
Variation ID: 12356 Accession: VCV000012356.82
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7674220 (GRCh38) [ NCBI UCSC ] 17: 7577538 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Aug 5, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.743G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg248Gln missense NM_000546.5(TP53):c.743G>A NM_001126112.3:c.743G>A NP_001119584.1:p.Arg248Gln missense NM_001126113.3:c.743G>A NP_001119585.1:p.Arg248Gln missense NM_001126114.3:c.743G>A NP_001119586.1:p.Arg248Gln missense NM_001126115.2:c.347G>A NP_001119587.1:p.Arg116Gln missense NM_001126116.2:c.347G>A NP_001119588.1:p.Arg116Gln missense NM_001126117.2:c.347G>A NP_001119589.1:p.Arg116Gln missense NM_001126118.2:c.626G>A NP_001119590.1:p.Arg209Gln missense NM_001276695.3:c.626G>A NP_001263624.1:p.Arg209Gln missense NM_001276696.3:c.626G>A NP_001263625.1:p.Arg209Gln missense NM_001276697.3:c.266G>A NP_001263626.1:p.Arg89Gln missense NM_001276698.3:c.266G>A NP_001263627.1:p.Arg89Gln missense NM_001276699.3:c.266G>A NP_001263628.1:p.Arg89Gln missense NM_001276760.3:c.626G>A NP_001263689.1:p.Arg209Gln missense NM_001276761.3:c.626G>A NP_001263690.1:p.Arg209Gln missense NC_000017.11:g.7674220C>T NC_000017.10:g.7577538C>T NG_017013.2:g.18331G>A LRG_321:g.18331G>A LRG_321t1:c.743G>A LRG_321p1:p.Arg248Gln P04637:p.Arg248Gln - Protein change
- R248Q, R116Q, R209Q, R89Q
- Other names
-
p.R248Q:CGG>CAG
NM_000546.6(TP53):c.743G>A
- Canonical SPDI
- NC_000017.11:7674219:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00006
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3367 | 3466 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Apr 12, 2023 | RCV000013150.35 | |
| Pathogenic (5) |
reviewed by expert panel
|
Aug 5, 2024 | RCV000197114.26 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2022 | RCV000115736.27 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000420727.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000419135.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000421194.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000420303.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000421893.9 | |
| Likely pathogenic (2) |
no assertion criteria provided
|
Aug 31, 2019 | RCV000424869.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000426359.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000427709.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148913.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432778.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432587.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000435533.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437291.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000417916.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438410.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437935.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000439963.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000426606.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000445244.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000433424.9 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2024 | RCV000235221.40 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437518.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000444656.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000426233.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000428591.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000430513.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000441226.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000445235.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785344.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2021 | RCV001527465.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763417.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 25, 2019 | RCV000790860.9 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV001270275.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 12, 2016 | RCV001789749.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 8, 2021 | RCV001554245.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255671.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2020 | RCV001257519.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV003996090.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162244.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003332079.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 20, 2023 | RCV003466852.1 | |
|
TP53-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 9, 2024 | RCV004745155.1 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 05, 2024)
|
reviewed by expert panel
Method: curation
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001142549.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024 |
Comment:
The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant … (more)
The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024) (less)
|
|
|
Likely pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266133.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jul 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785422.2
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894154.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821785.2
First in ClinVar: Oct 10, 2018 Last updated: May 04, 2020 |
Comment:
This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located … (more)
This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356). (less)
|
|
|
Likely pathogenic
(Jun 25, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449921.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: case-control
|
Familial cancer of breast
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV001450492.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 3
Age: 40-78 years
Sex: female
Geographic origin: Sri Lanka
|
|
|
Pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839112.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(Feb 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002525970.2
First in ClinVar: Jun 18, 2022 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Dec 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149645.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., … (more)
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644) (less)
|
|
|
Pathogenic
(Apr 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004017915.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056]. (less)
|
|
|
Pathogenic
(Jul 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206252.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134877.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686766.3
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 23, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847499.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, … (more)
The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic. (less)
|
|
|
Pathogenic
(Oct 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185472.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to … (more)
The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation. (less)
|
|
|
Pathogenic
(Feb 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198834.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585617.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Jun 09, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232078.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Sep 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363225.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four … (more)
Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841287.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Leukemia (present)
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253851.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 15, 2000)
|
no assertion criteria provided
Method: literature only
|
LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033397.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 of 8 families with Li-Fraumeni syndrome-1 (151623), Santibanez-Koref et al. (1991) identified mutations in the TP53 gene. One was the previously described arg248-to-trp … (more)
In 2 of 8 families with Li-Fraumeni syndrome-1 (151623), Santibanez-Koref et al. (1991) identified mutations in the TP53 gene. One was the previously described arg248-to-trp mutation (191170.0001). The second was a novel mutation in the same codon: a CGG-to-CAG change resulting in substitution of glutamine for arginine (R248Q). Each family had 2 individuals affected. In the arg248-to-trp family, one individual had breast cancer at age 33, and the other had rhabdomyosarcoma at age 3 and chondrosarcoma at age 16. In the arg248-to-gln family, one had bilateral breast cancer at age 25 and leiomyosarcoma at age 44, and the other had medulloblastoma at age 3 and osteosarcoma at age 8. Toguchida et al. (1992) also identified an arg248-to-gln change as a novel germline mutation in a patient with osteosarcoma who had had 2 primary tumors in her lifetime. At 17 years of age she was found to have osteosarcoma of the right femur, and 2 years later had an osteosarcoma of her right forearm. She was disease-free until the age of 28 years, when bilateral breast cancer was diagnosed. Orbital rhabdomyosarcoma developed in her daughter at the age of 5 years. Both the mother and the daughter had the same variant band on SSCP analysis of exon 7. The proband's parents lacked the abnormal band. In a family with features of Li-Fraumeni syndrome, Tachibana et al. (2000) identified a germline R248Q mutation in the p53 gene. Several family members developed glioblastoma multiforme (see 137800). (less)
|
|
|
Pathogenic
(Jul 24, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000190000.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
|
|
Pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Sarcoma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190659.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
|
Pathogenic
(Dec 27, 2012)
|
no assertion criteria provided
Method: research
|
Li-Fraumeni syndrome 1
GERMLINE
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Donald Williams Parsons Laboratory, Baylor College of Medicine
Additional submitter:
Donald Williams Parsons Laboratory, Baylor College of Medicine
Study: CSER-BASIC3
Accession: SCV000599966.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
Comment:
This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a … (more)
This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma). (less)
Number of individuals with the variant: 1
Family history: yes
Age: 0-9 years
Sex: female
Ethnicity/Population group: Causasians
|
|
|
Pathogenic
(Apr 12, 2016)
|
no assertion criteria provided
Method: research
|
Malignant Colorectal Neoplasm
Affected status: yes
Allele origin:
somatic
|
Genome Sciences Centre, British Columbia Cancer Agency
Study: Personalized OncoGenomics
Accession: SCV000693734.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923912.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
|
|
Likely pathogenic
(Jul 25, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Lymphoma
Affected status: yes
Allele origin:
somatic
|
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center
Accession: SCV000930032.1
First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
|
|
|
Likely pathogenic
(Aug 31, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Multiple myeloma
Affected status: yes
Allele origin:
somatic
|
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center
Accession: SCV001132099.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Apr 30, 2019)
|
no assertion criteria provided
Method: research
|
Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432236.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
|
|
|
Pathogenic
(Sep 01, 2020)
|
no assertion criteria provided
Method: provider interpretation
|
Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434345.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
|
|
Pathogenic
(Mar 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Ductal carcinoma in situ
Affected status: yes
Allele origin:
de novo
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738480.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021
Comment:
Variant observed at low frequency
|
Secondary finding: yes
|
|
|
Pathogenic
(Mar 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Familial cancer of breast
Affected status: no
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738502.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
|
Pathogenic
(Aug 08, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001774820.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Indication for testing: breast cancer
Age: 30-39 years
Sex: female
Comment on evidence:
Invasive ductal carcinoma EST receptor - PRO receptor - HER2 receptor -
|
|
|
Pathogenic
(Aug 26, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV002589035.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
|
|
|
Pathogenic
(Jul 01, 2021)
|
no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758165.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Malignant tumor of urinary bladder
Affected status: yes
Allele origin:
somatic
|
Laboratory of Urology, Hospital Clinic de Barcelona
Accession: SCV004040602.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Adrenocortical carcinoma
Affected status: no
Allele origin:
somatic
|
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University
Accession: SCV004046836.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
|
|
|
Pathogenic
(Aug 09, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TP53-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005357958.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with … (more)
The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant as pathogenic. (less)
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Carcinoma of esophagus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504695.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Glioblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504693.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504694.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504696.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of brain
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504697.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Myelodysplastic syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504698.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Acute myeloid leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504702.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Hepatocellular carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504704.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Gastric adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504703.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504699.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell carcinoma of the skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504700.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504701.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Ovarian serous cystadenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504705.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Transitional cell carcinoma of the bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504706.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504710.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Brainstem glioma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504712.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Prostate adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504711.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Pancreatic adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504707.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504708.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Uterine carcinosarcoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504709.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504713.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Medulloblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504714.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
B-cell chronic lymphocytic leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504718.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant neoplasm of body of uterus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504715.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Small cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504716.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple myeloma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504717.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692073.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(Aug 15, 2023)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV004026687 appears to be redundant with SCV005094408.
(less)
Notes: SCV004026687 appears to
(...more)
Source: NCBI
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004026687.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356).
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056].
Comment:
The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic.
Comment:
The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting
Comment:
Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).
Comment:
The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)
Comment:
This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356).
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056].
Comment:
The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic.
Comment:
The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting
Comment:
Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).
Comment:
The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
| Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India. | Narang A | Human mutation | 2020 | PMID: 32906206 |
| Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients. | Manoharan V | BMC cancer | 2020 | PMID: 32000721 |
| Divergent clonal evolution of a common precursor to mantle cell lymphoma and classic Hodgkin lymphoma. | Tashkandi H | Cold Spring Harbor molecular case studies | 2019 | PMID: 31395597 |
| Genotype-phenotype associations among panel-based TP53+ subjects. | Rana HQ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31105275 |
| Hematologic malignancies and Li-Fraumeni syndrome. | Swaminathan M | Cold Spring Harbor molecular case studies | 2019 | PMID: 30709875 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| Identification and characterization of TP53 gene Allele Dropout in Li-Fraumeni syndrome and Oral cancer cohorts. | Haque MM | Scientific reports | 2018 | PMID: 30076369 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| Inherited DNA-Repair Defects in Colorectal Cancer. | AlDubayan SH | American journal of human genetics | 2018 | PMID: 29478780 |
| Molecular characterization of ERBB2-amplified colorectal cancer identifies potential mechanisms of resistance to targeted therapies: a report of two instructive cases. | Owen DR | Cold Spring Harbor molecular case studies | 2018 | PMID: 29438965 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28369373 |
| Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors. | Sherborne AL | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 27683180 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. | Parsons DW | JAMA oncology | 2016 | PMID: 26822237 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| Transmission of germline TP53 mutations from male carriers to female partners. | Patrier-Sallebert S | Journal of medical genetics | 2015 | PMID: 25612911 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing. | Behjati S | PloS one | 2014 | PMID: 24810334 |
| Mutant p53 in cancer: new functions and therapeutic opportunities. | Muller PA | Cancer cell | 2014 | PMID: 24651012 |
| Prognostic significance of TP53 mutations and single nucleotide polymorphisms in acute myeloid leukemia: a case series and literature review. | Zeichner SB | Asian Pacific journal of cancer prevention : APJCP | 2014 | PMID: 24641375 |
| Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. | Rossi D | Blood | 2014 | PMID: 24501221 |
| Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. | Kihara R | Leukemia | 2014 | PMID: 24487413 |
| Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. | Stoddart A | Blood | 2014 | PMID: 24381225 |
| Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. | Hanel W | Cell death and differentiation | 2013 | PMID: 23538418 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. | Leroy B | Nucleic acids research | 2013 | PMID: 23161690 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant. | Barakat K | PloS one | 2011 | PMID: 22110706 |
| Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. | Villani A | The Lancet. Oncology | 2011 | PMID: 21601526 |
| Gastric cancer in individuals with Li-Fraumeni syndrome. | Masciari S | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21552135 |
| TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. | Xu J | Nature chemical biology | 2011 | PMID: 21445056 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. | Wu CC | Human genetics | 2011 | PMID: 21305319 |
| Mutant p53 R248Q but not R248W enhances in vitro invasiveness of human lung cancer NCI-H1299 cells. | Yoshikawa K | Biomedical research (Tokyo, Japan) | 2010 | PMID: 21187651 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights. | Merabet A | The Biochemical journal | 2010 | PMID: 20113312 |
| High frequency of de novo mutations in Li-Fraumeni syndrome. | Gonzalez KD | Journal of medical genetics | 2009 | PMID: 19556618 |
| Li-Fraumeni and Li-Fraumeni-like syndrome mutations in p53 are associated with exonic methylation and splicing regulatory elements. | Kouidou S | Molecular carcinogenesis | 2009 | PMID: 19367569 |
| Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. | Bougeard G | Journal of medical genetics | 2008 | PMID: 18511570 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB. | Benoit V | Oncogene | 2006 | PMID: 16682957 |
| The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. | Olivier M | Clinical cancer research : an official journal of the American Association for Cancer Research | 2006 | PMID: 16489069 |
| Mutant p53 proteins bind DNA in a DNA structure-selective mode. | Göhler T | Nucleic acids research | 2005 | PMID: 15722483 |
| Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. | Bendig I | Cancer genetics and cytogenetics | 2004 | PMID: 15381368 |
| Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. | Chan KT | Cancer chemotherapy and pharmacology | 2004 | PMID: 15004724 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. | Vahteristo P | Cancer research | 2001 | PMID: 11479205 |
| Use of mutation spectra analysis software. | Rogozin I | Human mutation | 2001 | PMID: 11180592 |
| Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. | Rapakko K | British journal of cancer | 2001 | PMID: 11139324 |
| Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma. | Tachibana I | American journal of medical genetics | 2000 | PMID: 10797439 |
| Hot-spot mutants of p53 core domain evince characteristic local structural changes. | Wong KB | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10411893 |
| Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. | Lomax ME | Oncogene | 1998 | PMID: 9704930 |
| Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer. | Berns EM | British journal of cancer | 1998 | PMID: 9569050 |
| Identification of human p53 mutations with differential effects on the bax and p21 promoters using functional assays in yeast. | Flaman JM | Oncogene | 1998 | PMID: 9546439 |
| Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. | Varley JM | Cancer research | 1997 | PMID: 9242456 |
| Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. | Frebourg T | American journal of human genetics | 1995 | PMID: 7887414 |
| Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. | Birch JM | Cancer research | 1994 | PMID: 8118819 |
| Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. | Ory K | The EMBO journal | 1994 | PMID: 8062826 |
| Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. | Cho Y | Science (New York, N.Y.) | 1994 | PMID: 8023157 |
| Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. | Toguchida J | The New England journal of medicine | 1992 | PMID: 1565143 |
| p53 germline mutations in Li-Fraumeni syndrome. | Santibáñez-Koref MF | Lancet (London, England) | 1991 | PMID: 1683921 |
| Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. | Malkin D | Science (New York, N.Y.) | 1990 | PMID: 1978757 |
| http://docm.genome.wustl.edu/variants/ENST00000269305:c.743G>A | - | - | - | - |
| http://p53.iarc.fr/ | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TP53 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed | - | - | - | - |
| click to load more click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Jul 31, 2024 | RCV000426606.10 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094408.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
The NM_000546.6: c.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)
Comment:
This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356).
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression and apoptotic activities, dominant-negative effect (Lomax et al., 1998; Kato et al., 2003; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24573247, 23334668, 21305319, 9704930, 15004724, 7718482, 12124823, 15541116, 9738975, 16322298, 8252037, 17606709, 22851211, 2263646, 26787237, 29300620, 29489754, 20128691, 21343334, 22110706, 24651015, 21761402, 19367569, 18048389, 8080050, 16861262, 18555592, 10557074, 10567903, 10914716, 16142349, 8707423, 10519380, 12917626, 10753186, 8062826, 7682763, 1915267, 7478555, 16959974, 12509970, 26703669, 28154273, 27153395, 26822237, 28724667, 28369373, 28125075, 29979965, 29478780, 28861920, 23538418, 30076369, 29752822, 26556299, 28975465, 29753700, 30092803, 30720243, 30093976, 30840781, 30553995, 31159747, 31081129, 19012332, 1565143, 25612911, 21601526, 7887414, 24810334, 27683180, 30709875, 15510160, 21552135, 1458490, 16778209, 10754498, 12826609, 31105275, 31447099, 32029870, 33818021, 33300245, 31851316, 32658383, 30982232, 33245408, 30875412, 32427313, 33674644)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15381368, 1565143, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 8023157, 10411893, 23538418, 21445056].
Comment:
The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple Li-Fraumeni syndrome families (PMID: 21305319 (2011), 21601526 (2011), 17606709 (2007), 7887414 (1995), 1565143 (1992), 9242456 (1997)), as well as in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/TP53)). Additionally, this variant has been shown to affect DNA binding and transactivation activities (PMID: 21343334 (2011), 20128691 (2010), 17606709 (2007)), as well as shown to have a dominant negative effect (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with glutamine at codon 248 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in DNA binding and transactivation assays (PMID: 9704930, 12826609, 20128691, 21343334, 23538418, 28369373), and defective in cell growth inhibition, apoptosis, and proliferation assays (PMID: 9704930, 21187651, 29979965, 30224644). This variant has been reported in numerous individuals affected with Li-Fraumeni syndrome (PMID: 1565143, 1683921, 7887414, 9242456, 10797439, 11139324, 11479205, 17606709, 18511570, 19556618, 21305319, 21552135, 21601526, 25612911, 26822237, 27683180 ) and breast cancer (PMID: 11139324, 16489069, 21761402, 30287823, 32000721, 33471991). It also has been observed de novo in Li Fraumeni patients with paternity confirmed (PMID: 15381368, 24810334). This variant has been identified in 3/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The Arg248Gln is a recurrent variant in TP53 which has been reported in more than 10 individuals with Li-Fraumeni syndrome (LFS; Santibanez-Koref 1991, Toguchida 1992, Frebourg 1995, Marsciari 2011, Villani 2011, Wu 2011, IARC TP53 Database). This variant shows moderate segration with disease among affected family members (>5 meiosis) and was absent from over 400 control choromosomes (Toguchida, 1992). In addition this variant is predicited to create a new splice site which could disrupt protein function or lead to absent protein (Kouidou 2009). Based on this information, this variant is highly likely to be pathogenic.
Comment:
The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. This alteration has been described as a de novo mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med. 1992 May 14;326(20):1301-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
TP53: PP1:Strong, PM1, PM2, PM5, PS3:Moderate, PS4:Supporting
Comment:
Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012356 / PMID: 1565143). The variant has been previously reported as de novo in a similarly affected individual (PMID: 15381368). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15381368, 1565143, 7887414, 9242456). Different missense changes at the same codon (p.Arg248Gly, p.Arg248Leu, p.Arg248Pro, p.Arg248Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012347, VCV000230253, VCV000237954, VCV000376652, VCV000437017 / PMID: 11180592, 1978757, 28152038, 31105275). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 248 of the TP53 protein (p.Arg248Gln). This variant is present in population databases (rs11540652, gnomAD 0.006%). This missense change has been observed in individual(s) with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 7887414, 17606709, 21305319, 21601526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12356). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 17606709, 20128691, 21343334). This variant disrupts the p.Arg248 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8062826, 9546439, 12826609, 15722483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).
Comment:
The TP53 c.743G>A variant is predicted to result in the amino acid substitution p.Arg248Gln. This variant is well documented in the literature in individuals with Li-Fraumeni syndrome and various cancers including breast cancer and osteosarcoma (see for example: Stjepanovic. 2018. PubMed ID: 30092803; Wu. 2011. PubMed ID: 21305319; Monti. 2007. PubMed ID: 17606709; Toguchida. 1992. PubMed ID: 1565143; Guindalini. 2022. PubMed ID: 35264596). In vitro experiments have shown the c.743G>A variant results in a dominant-negative allele, and reduces p53 protein activity by ~75% compared to wild-type (Monti. 2011. PubMed ID: 21343334; Zerdoumi. 2017. PubMed ID: 28369373). This variant is reported to segregate with disease within families (Monti. 2007. PubMed ID: 17606709; Wu. 2011. PubMed ID: 21305319), and has been reported to arise as a de novo mosaic germline variant that was later found to be homozygous in numerous tumor samples (Behjati. 2014. PubMed ID: 24810334). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 Variant Curation Expert Panel (VCEP; https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf887752-8539-4177-a74d-dc5c8f8a36ed), and is classified as pathogenic and likely pathogenic by many other labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12356/). We interpret this variant as pathogenic.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs11540652 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.