Submissions for variant NM_000546.6(TP53):c.221C>T (p.Ala74Val)

gnomAD frequency: 0.00001  dbSNP: rs587781832

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000816275	SCV001429625	likely benign	Li-Fraumeni syndrome	2020-08-11	reviewed by expert panel	curation	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). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in >8 60+ year old females without a cancer diagnosis (BS2; Internal laboratory contributor. In summary, TP53 c.221C>T (p.Ala74Val) 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: BS3; BP4;BS2_Supporting.
Ambry Genetics	RCV000130119	SCV000184950	likely benign	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000487230	SCV000570633	uncertain significance	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.221C>T at the cDNA level, p.Ala74Val (A74V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. This variant is reported as having functional transactivation activity in the International Agency for Research on Cancer (IARC) TP53 database based on functional studies by Kato et al. (2003). TP53 Ala74Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Ala74Val is located in the SH3 Domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Ala74Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000816275	SCV000956775	uncertain significance	Li-Fraumeni syndrome	2023-09-10	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 74 of the TP53 protein (p.Ala74Val). This variant is present in population databases (rs587781832, gnomAD 0.01%). 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: 141547). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (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 Diagnostics, LLC DBA Color Health	RCV000130119	SCV001736273	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 74 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 that this variant protein is functional in yeast transactivation activity assay and in human cells (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/281908 chromosomes 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493453	SCV004242762	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing