ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.428T>C (p.Val143Ala)

dbSNP: rs1555526241
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000991143 SCV001142543 likely pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). Additionally, there was a de novo observation in an individual with adrenocortical carcinoma without mention of parental confirmation (PM6; PMID: 19701813). In summary, TP53 c.428T>C; p.Val143Ala meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PS3, PM6.
Invitae RCV000991143 SCV002236013 pathogenic Li-Fraumeni syndrome 2022-10-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 804214). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 19701813, 25318593, 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 143 of the TP53 protein (p.Val143Ala).
Myriad Genetics, Inc. RCV004030120 SCV004933938 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8458321, 8013454, 10435620]. This variant is expected to disrupt protein structure [17015838].

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