Submissions for variant NM_000546.6(TP53):c.251C>T (p.Ala84Val)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002433030	SCV002742017	likely benign	Hereditary cancer-predisposing syndrome	2021-05-17	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017935	SCV004847410	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	The p.Ala84Val variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 1792511). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
Baylor Genetics	RCV004571148	SCV005054345	uncertain significance	Adrenocortical carcinoma, hereditary	2023-12-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005098175	SCV005732501	uncertain significance	Li-Fraumeni syndrome	2024-02-24	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 84 of the TP53 protein (p.Ala84Val). 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: 1792511). Advanced modeling performed at Invitae incorporating data from internal and/or published 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%. 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.