VCV000237941.25 - ClinVar

NM_000546.6(TP53):c.11C>T (p.Pro4Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

5 conditions

Reviewed by expert panel

Likely benign

Aug 2021 by ClinGen TP53 V… FDA Recognized Database

for None

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.11C>T (p.Pro4Leu)

Variation ID: 237941 Accession: VCV000237941.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7676584 (GRCh38) [ NCBI UCSC ] 17: 7579902 (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	May 26, 2018	May 1, 2024	Aug 4, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.11C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Pro4Leu	missense
NM_001126112.3:c.11C>T	NP_001119584.1:p.Pro4Leu	missense
NM_001126113.3:c.11C>T	NP_001119585.1:p.Pro4Leu	missense
NM_001126114.3:c.11C>T	NP_001119586.1:p.Pro4Leu	missense
NM_001126118.2:c.-224C>T		5 prime UTR
NM_001276695.3:c.-107C>T		5 prime UTR
NM_001276696.3:c.-107C>T		5 prime UTR
NM_001276760.3:c.-107C>T		5 prime UTR
NM_001276761.3:c.-107C>T		5 prime UTR
NC_000017.11:g.7676584G>A
NC_000017.10:g.7579902G>A
NG_017013.2:g.15967C>T
LRG_321:g.15967C>T
LRG_321t1:c.11C>T	LRG_321p1:p.Pro4Leu

... more HGVS ... less HGVS

Protein change

P4L

Other names

NM_000546.5(TP53):c.11C>T
p.Pro4Leu

Canonical SPDI

NC_000017.11:7676583:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA10583686 dbSNP: rs878854064 VarSome

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
Gene	OMIM	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.
Li-Fraumeni syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000229754.16
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 21, 2021	RCV000571530.10
Li-Fraumeni syndrome 1	Likely benign (3)	reviewed by expert panel	Aug 4, 2021	RCV000662489.5
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 14, 2019	RCV000759369.5
not specified	Uncertain significance (1)	criteria provided, single submitter	Oct 23, 2023	RCV000780782.5

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.
Likely benign (Aug 04, 2021)	reviewed by expert panel (ClinGen TP53 ACMG Specifications v1.2) Method: curation	None (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen TP53 Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001949907.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (2) PubMed: 12826609‚ 30224644 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/410f531a-d916-4dbc-9751-ea42adb439f2 Comment: This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 … (more) This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.11C>T (p.Pro4Leu) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3. (less)
Uncertain significance (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000285174.9 First in ClinVar: Jul 03, 2016 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 12826609‚ 29979965‚ 30224644 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TP53 protein (p.Pro4Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TP53 protein (p.Pro4Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 237941). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely benign (Jan 21, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000672384.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 12826609‚ 30224644 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Mar 03, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000784994.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018	Publications: PubMed (1) PubMed: 12826609
Uncertain significance (Jan 14, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888659.3 First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022	Publications: PubMed (2) PubMed: 30181807‚ 12826609
Uncertain significance (Apr 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001349332.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022	Comment: This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in yeast has shown that this variant does not impair transcriptional transactivation activity of TP53 (IARC database; PMID: 12826609). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Apr 11, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004017881.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Oct 23, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918324.3 First in ClinVar: Jun 02, 2019 Last updated: Nov 20, 2023	Publications: PubMed (23) PubMed: 17606709‚ 21343334‚ 20407015‚ 22722193‚ 12826609‚ 26230955‚ 21519010‚ 27463065‚ 25952993‚ 22186996‚ 27680515‚ 27959731‚ 16818505‚ 27895058‚ 30327374‚ 11782540‚ 23246812‚ 22915647‚ 26585234‚ 27276561‚ 31365877‚ 30181807‚ 30224644 Comment: Variant summary: TP53 c.11C>T (p.Pro4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: TP53 c.11C>T (p.Pro4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250676 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11C>T has been reported in the literature in an individual affected with breast cancer, however it was identified as a somatic variant (Ellis_2012; COSMIC). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be functional based on transcriptional activity in yeast (Kato 2003). In addition, a loss-of-function saturation mutagenesis screen indicated that this missense does not substantially affect TP53 function (Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 22722193, 12826609, 30224644). Seven other submitters, including an expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=5) or likely benign (n=2; including the expert panel). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
Uncertain Significance (Sep 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004823874.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 12826609 Comment: This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in yeast has shown that this variant does not impair transcriptional transactivation activity of TP53 (IARC database; PMID: 12826609). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 1

Comment:

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.11C>T (p.Pro4Leu) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TP53 protein (p.Pro4Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 237941). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This missense variant replaces proline with leucine at codon 4 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study in yeast has shown that this variant does not impair transcriptional transactivation activity of TP53 (IARC database; PMID: 12826609). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Variant summary: TP53 c.11C>T (p.Pro4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250676 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11C>T has been reported in the literature in an individual affected with breast cancer, however it was identified as a somatic variant (Ellis_2012; COSMIC). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be functional based on transcriptional activity in yeast (Kato 2003). In addition, a loss-of-function saturation mutagenesis screen indicated that this missense does not substantially affect TP53 function (Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 22722193, 12826609, 30224644). Seven other submitters, including an expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=5) or likely benign (n=2; including the expert panel). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Comment:

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas.	Donehower LA	Cell reports	2019	PMID: 31365877
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes.	McNamara CJ	Blood advances	2018	PMID: 30327374
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
Metastases risk in thin cutaneous melanoma: prognostic value of clinical-pathologic characteristics and mutation profile.	Richetta AG	Oncotarget	2018	PMID: 30181807
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.	Döhner H	Blood	2017	PMID: 27895058
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
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
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
A novel hierarchical prognostic model of AML solely based on molecular mutations.	Grossmann V	Blood	2012	PMID: 22915647
Whole-genome analysis informs breast cancer response to aromatase inhibition.	Ellis MJ	Nature	2012	PMID: 22722193
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
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
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.	Monti P	Molecular cancer research : MCR	2011	PMID: 21343334
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
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
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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/410f531a-d916-4dbc-9751-ea42adb439f2	-	-	-	-
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Text-mined citations for rs878854064 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.11C>T (p.Pro4Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs878854064 ...