Submissions for variant NM_000546.6(TP53):c.217G>A (p.Val73Met)

gnomAD frequency: 0.00011  dbSNP: rs587782423

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000553568	SCV001142542	likely benign	Li-Fraumeni syndrome	2023-03-08	reviewed by expert panel	curation	This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show retained 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.217G>A; p.Val73Met 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: BP4, BS3.
Ambry Genetics	RCV000131474	SCV000186461	likely benign	Hereditary cancer-predisposing syndrome	2018-12-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000553568	SCV000629791	likely benign	Li-Fraumeni syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131474	SCV000903922	likely benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986048	SCV001134863	likely benign	not provided	2021-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192621	SCV001360871	benign	not specified	2021-03-07	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.217G>A (p.Val73Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250502 control chromosomes. The observed variant frequency is approximately 1.71 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.217G>A in individuals affected with Li-Fraumeni Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Kato_2003, PHANTM database). Four clinical diagnostic laboratories and one expert panel (ClinGen TP53 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=2 to include the expert panel; likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000986048	SCV001824878	likely benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33300245, 30840781, 30287823, 14559903, 26296696)
Genetic Services Laboratory, University of Chicago	RCV001192621	SCV002065423	likely benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192621	SCV004242763	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing