Submissions for variant NM_000546.6(TP53):c.257C>T (p.Ala86Val)

dbSNP: rs1597374264

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810093	SCV000950281	uncertain significance	Li-Fraumeni syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 86 of the TP53 protein (p.Ala86Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hepatocellular carcinoma (PMID: 23713777). ClinVar contains an entry for this variant (Variation ID: 654187). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 23713777). 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	RCV001525077	SCV001735088	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 86 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit normal TP53 function in a yeast transactivation assay (IARC, PMID: 12826609) and in a human cell growth suppression assay (PMID: 30224644). This variant has not been reported in individuals affected with Li-fraumeni syndrome in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001525077	SCV002582133	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290457	SCV002582695	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001525077	SCV002739142	likely benign	Hereditary cancer-predisposing syndrome	2022-10-25	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.