ClinVar Miner

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

gnomAD frequency: 0.00010  dbSNP: rs587782423
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000553568 SCV001142542 benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a minor allele frequency of 0.0005178 (0.05%, 13/25,106 alleles) in the European (Finnish) subpopulation of the gnomAD cohort (BS1). 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 benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BP4, BS3.
Ambry Genetics RCV000131474 SCV000186461 likely benign Hereditary cancer-predisposing syndrome 2018-12-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
Invitae RCV000553568 SCV000629791 likely benign Li-Fraumeni syndrome 2021-11-29 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

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