ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.706T>C (p.Tyr236His)

dbSNP: rs587782289
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000198628 SCV000254636 pathogenic Li-Fraumeni syndrome 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 236 of the TP53 protein (p.Tyr236His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216469). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492107 SCV000581165 pathogenic Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing The p.Y236H variant (also known as c.706T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 706. The tyrosine at codon 236 is replaced by histidine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and deficient growth suppression in functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one family within our clinical cohort (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). Another missense alteration at this codon (p.Y236C) has also been reported in a Li-Fraumeni syndrome patient and functional assays have shown it to be a severely-deficient, dominant-negative mutation (Rines R et al. Carcinogenesis. 1998 Jun;19(6):979-84; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9). Based on the available evidence, p.Y236H is classified as a pathogenic mutation.
Myriad Genetics, Inc. RCV004020463 SCV004931305 likely pathogenic Li-Fraumeni syndrome 1 2024-02-16 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

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