ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.217G>A (p.Val73Met) (rs587782423)

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Total submissions: 6
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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 Insufficient or conflicting evidence;Other strong data supporting benign classification;In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000553568 SCV000629791 uncertain significance Li-Fraumeni syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 73 of the TP53 protein (p.Val73Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs587782423, ExAC 0.06%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 142386). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
Color RCV000131474 SCV000903922 benign Hereditary cancer-predisposing syndrome 2016-08-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986048 SCV001134863 likely benign not provided 2018-12-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192621 SCV001360871 likely benign not specified 2019-09-23 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 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), 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). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign/likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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