Submissions for variant NM_000179.3(MSH6):c.3656C>T (p.Thr1219Ile)

dbSNP: rs63750949

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572978	SCV000676115	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	clinical testing	The p.T1219I variant (also known as c.3656C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3656. The threonine at codon 1219 is replaced by isoleucine, an amino acid with similar properties. This variant has been identified in at least two families meeting Amsterdam criteria, including one patient with MSI-H colorectal cancer at 37 showing intact MSH6 staining on IHC; this same patient was also diagnosed with complex non-atypical endometrial hyperplasia at 43 (Berends MJ et al. Am J Hum Genet, 2002 Jan;70:26-37; Ikenoue T et al. J Hum Genet, 2019 Dec;64:1187-1194). In addition, this variant has demonstrated reduced mismatch repair activity in an in vitro complementation assay (Drost M et al. Hum Mutat, 2012 Mar;33:488-94). In another functional assay, MSH6 protein levels remained relatively high, but this variant abrogated MMR activity in mouse embryonic stem cells (Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222841	SCV001394961	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 1219 of the MSH6 protein (p.Thr1219Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Lynch syndrome (PMID: 11709755). ClinVar contains an entry for this variant (Variation ID: 89442). This variant has been reported to affect MSH6 protein function (PMID: 28531214). 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.
Myriad Genetics, Inc.	RCV003450976	SCV004189261	likely pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22102614]. This variant is expected to disrupt protein structure [Myriad internal data].