ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.364G>A (p.Val122Met)

dbSNP: rs587781495
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV001527079 SCV001737914 likely benign Li-Fraumeni syndrome 1 2021-06-02 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a partially functional variant according to Kato, et al. and there are two additional in vitro assays demonstrating retained function (BS3_Supporting; PMID: 12826609, 30224644, 25584008). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.364G>A (p.Val122Met) 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, BS3_Supporting, BP4, BS2_Supporting. PM2_Supporting should not be considered conflicting evidence as there is sufficient evidence to classify as Likely Benign.
Ambry Genetics RCV000129460 SCV000184230 likely benign Hereditary cancer-predisposing syndrome 2022-05-26 criteria provided, single submitter clinical testing 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.
Invitae RCV000206482 SCV000259560 uncertain significance Li-Fraumeni syndrome 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 122 of the TP53 protein (p.Val122Met). 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: 141101). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 15781620, 29979965). 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 Diagnostics, LLC DBA Color Health RCV000129460 SCV000908796 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000581285 SCV000692092 uncertain significance not specified no assertion criteria provided clinical testing

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