Submissions for variant NM_000546.6(TP53):c.188C>T (p.Ala63Val)

gnomAD frequency: 0.00001  dbSNP: rs372201428

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000467874	SCV001737942	benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.188C>T variant in TP53 is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 63 (p.Ala63Val). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor: Invitae). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.099; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1; 1/16/2025).
GeneDx	RCV000213047	SCV000211735	uncertain significance	not provided	2017-11-02	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.188C>T at the cDNA level, p.Ala63Val (A63V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Ala63Val 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 Ala63Val occurs at a position that is not conserved and is located in the SH3 Domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Ala63Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000161018	SCV000215136	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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467874	SCV000545312	uncertain significance	Li-Fraumeni syndrome	2025-01-02	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 63 of the TP53 protein (p.Ala63Val). This variant is present in population databases (rs372201428, gnomAD 0.02%). 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: 182922). 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, 30224644). 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.
Counsyl	RCV000663264	SCV000786495	uncertain significance	Li-Fraumeni syndrome 1	2018-05-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000161018	SCV000908800	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264516	SCV001442710	uncertain significance	not specified	2020-10-22	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.188C>T (p.Ala63Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251036 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.188C>T in individuals affected with Li-Fraumeni Syndrome has been reported. Several publications however report this variant as likely benign among variants detected in the gnomAD/ExAC datasets (example, de Andrade_2017, de Andrade_2019). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance, some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000663264	SCV004017876	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000467874	SCV004823839	uncertain significance	Li-Fraumeni syndrome	2023-08-15	criteria provided, single submitter	clinical testing