ClinVar Miner

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

dbSNP: rs672601296
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Total submissions: 7
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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 2020-08-11 reviewed by expert panel curation 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). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, the clinical significance of TP53 c.886C>T (p.His296Tyr) is likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, PM2_Supporting.
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)
Invitae RCV000633378 SCV000754600 uncertain significance Li-Fraumeni syndrome 2023-10-13 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). 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, 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.
Laboratory of Translational Genomics, National Cancer Institute RCV000119375 SCV000154282 not provided Sarcoma no assertion provided not provided

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