Submissions for variant NM_000546.6(TP53):c.886C>T (p.His296Tyr)

dbSNP: rs672601296

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000633378	SCV001429621	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.886C>T variant in TP53 is a missense variant predicted to cause substitution of Histidine by Tyrosine at amino acid 296 (p.His296Tyr). 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). This variant has an allele frequency of 0.000001695 (2/1180034 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Computational predictor scores (BayesDel = -0.12; 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 likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, PM2_Supporting, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025)
GeneDx	RCV000486480	SCV000571798	likely benign	not provided	2021-02-24	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33363700, 30224644)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633378	SCV000754600	uncertain significance	Li-Fraumeni syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 296 of the TP53 protein (p.His296Tyr). 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: 132973). 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.
Color Diagnostics, LLC DBA Color Health	RCV000774785	SCV000908783	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000774785	SCV002682774	likely benign	Hereditary cancer-predisposing syndrome	2020-02-11	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987365	SCV004804248	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.886C>T (p.His296Tyr) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251494 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.886C>T has been reported in the literature in at least one individual affected with breast cancer (e.g., Dorling_2021) as well as in the International Association for Research on Cancer (IARC) database (e.g., Giacomelli_2018). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 12826609, 33471991). ClinVar contains an entry for this variant (Variation ID: 132973). Based on the evidence outlined above, the variant was classified as uncertain significance.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV005089588	SCV005848144	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-11	criteria provided, single submitter	curation	According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PM2 (supporting pathogenic): v4: 0.000001695, BP4 (supporting benign): BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0, BS3 (strong benign): Transactivation assays show 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).
Laboratory of Translational Genomics, National Cancer Institute	RCV000119375	SCV000154282	not provided	Sarcoma		no assertion provided	not provided