NM_000546.6(TP53):c.869G>A (p.Arg290His) AND Li-Fraumeni syndrome

Germline classification:: Benign (5 submissions)
Last evaluated:: Aug 5, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000148914.37

Allele description [Variation Report for NM_000546.6(TP53):c.869G>A (p.Arg290His)]

NM_000546.6(TP53):c.869G>A (p.Arg290His)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.869G>A (p.Arg290His)

Other names:

p.R290H:CGC>CAC

HGVS:

NC_000017.11:g.7673751C>T
NG_017013.2:g.18800G>A
NM_000546.6:c.869G>AMANE SELECT
NM_001126112.3:c.869G>A
NM_001126113.3:c.869G>A
NM_001126114.3:c.869G>A
NM_001126115.1:c.473G>A
NM_001126115.2:c.473G>A
NM_001126116.2:c.473G>A
NM_001126117.2:c.473G>A
NM_001126118.2:c.752G>A
NM_001276695.3:c.752G>A
NM_001276696.3:c.752G>A
NM_001276697.3:c.392G>A
NM_001276698.3:c.392G>A
NM_001276699.3:c.392G>A
NM_001276760.3:c.752G>A
NM_001276761.3:c.752G>A
NP_000537.3:p.Arg290His
NP_000537.3:p.Arg290His
NP_001119584.1:p.Arg290His
NP_001119585.1:p.Arg290His
NP_001119586.1:p.Arg290His
NP_001119587.1:p.Arg158His
NP_001119588.1:p.Arg158His
NP_001119589.1:p.Arg158His
NP_001119590.1:p.Arg251His
NP_001263624.1:p.Arg251His
NP_001263625.1:p.Arg251His
NP_001263626.1:p.Arg131His
NP_001263627.1:p.Arg131His
NP_001263628.1:p.Arg131His
NP_001263689.1:p.Arg251His
NP_001263690.1:p.Arg251His
LRG_321t1:c.869G>A
LRG_321:g.18800G>A
LRG_321p1:p.Arg290His
NC_000017.10:g.7577069C>T
NM_000546.4:c.869G>A
NM_000546.5(TP53):c.869G>A
NM_000546.5:c.869G>A
P04637:p.Arg290His
p.R290H

Protein change:

R131H

Links:

UniProtKB: P04637#VAR_045411; dbSNP: rs55819519

NCBI 1000 Genomes Browser:

rs55819519

Molecular consequence:

NM_000546.6:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.869G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.392G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.752G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Tssr30535 AND (alive[prop]) (0)
Gene
GAA [Tympanuchus pallidicinctus]
GAA [Tympanuchus pallidicinctus]
Gene ID:128082886

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190660	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Uncertain significance (Jun 1, 2014)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000254643	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000886455	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Likely benign (Mar 28, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001142524	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0)	Benign (Aug 5, 2024)	germline	curation	Citation Link,
SCV001439185	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Benign (Sep 3, 2020)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	1	not provided	not provided	yes	clinical testing, research, curation

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190660.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254643.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000886455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	yes	research	PubMed (1)

Description

The TP53 variant designated as NM_000546.5:c.896G>A (p.R290H) is classified as likely benign in the context of Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Computational programs predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. Additionaly, the familial germline TP53 variant (NM_000546.5:c.869G>A, p.R290H) was detected in breast tumor tissue without evidence of loss of heterozygosity. No second somatic mutation was identified in TP53. The absence of loss of heterozygosity or second TP53 mutation in the tumor provides some evidence that the TP53 variant is more likely to be benign. We cannot rule out the possibility that this variant does cause some increased risk for breast cancer. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	1	not provided

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001142524.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001439185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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