ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1102C>T (p.His368Tyr)

dbSNP: rs786204227
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV001527083 SCV001737922 likely benign Li-Fraumeni syndrome 1 2021-04-19 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant 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_Supporting; PMID: 12826609, 30224644). In summary, TP53 c.1102C>T (p.His368Tyr) 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: PM2_Supporting, BP4, BS3_Supporting. PM2_Supporting should not be considered conflicting evidence as the variant otherwise meets criteria for Likely Benign classification.
Invitae RCV000168367 SCV000219057 uncertain significance Li-Fraumeni syndrome 2024-01-23 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 368 of the TP53 protein (p.His368Tyr). 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: 188342). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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.
Ambry Genetics RCV000222357 SCV000276938 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-27 criteria provided, single submitter clinical testing The p.H368Y variant (also known as c.1102C>T), located in coding exon 10 of the TP53 gene, results from a C to T substitution at nucleotide position 1102. The histidine at codon 368 is replaced by tyrosine, an amino acid with similar properties. This variant is in the C-terminal regulatory domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in a yeast based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is poorly conserved and tyrosine is the reference amino acid in several mammalian species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000222357 SCV000911486 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing

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