Submissions for variant NM_000546.6(TP53):c.188C>G (p.Ala63Gly)

gnomAD frequency: 0.00003  dbSNP: rs372201428

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001723801	SCV001949917	likely benign	Li-Fraumeni syndrome 1	2021-08-05	reviewed by expert panel	curation	Transactivation assays show retained/supertransactivation 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 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.188C>G (p.Ala63Gly) meets criteria for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.
Ambry Genetics	RCV000216082	SCV000272992	likely benign	Hereditary cancer-predisposing syndrome	2020-10-22	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.
Invitae	RCV000465288	SCV000545280	uncertain significance	Li-Fraumeni syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 63 of the TP53 protein (p.Ala63Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphocytic leukemia (PMID: 29300620). ClinVar contains an entry for this variant (Variation ID: 229693). 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%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587780	SCV000697433	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The c.188C>G (p.Ala63Gly) in TP53 gene is a missense variant involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is located within the mSin3a binding site, which is required for stabilization of p53 protein. In the functional study A63G was able to bind to mSin3a and thus prevent p53 from degradation. The variant is absent from control population datasets of ExAC and gnomAD. To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614877	SCV000712636	uncertain significance	not specified	2016-11-22	criteria provided, single submitter	clinical testing	The p.Ala63Gly variant in TP53 has not been previously reported as a germline va riant in individuals with Li-Fraumeni syndrome or in large population studies. C omputational prediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala63Gly variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000216082	SCV000908801	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	This variant is located in 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 behaves like wild-type in yeast transactivation studies and human cell growth suppression assays (PMID: 11359905, 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/31376 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.
GeneDx	RCV000587780	SCV001812994	uncertain significance	not provided	2019-12-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: functional transactivation, as reported by the International Agency for Research on Cancer TP53 database (Kato 2003); This variant is associated with the following publications: (PMID: 30886117, 30224644, 12826609, 15450421, 11024481, 11359905, 14559903)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587780	SCV004221346	likely benign	not provided	2023-04-11	criteria provided, single submitter	clinical testing