Submissions for variant NM_000179.3(MSH6):c.3632T>C (p.Leu1211Pro)

dbSNP: rs864622041

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000206750	SCV000259176	pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000215362	SCV000273358	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-31	criteria provided, single submitter	clinical testing	The p.L1211P pathogenic mutation (also known as c.3632T>C), located in coding exon 7 of the MSH6 gene, results from a T to C substitution at nucleotide position 3632. The leucine at codon 1211 is replaced by proline, an amino acid with similar properties. This alteration was reported in a Brazilian family suspected of having Lynch syndrome (Rossi BM et al. BMC Cancer. 2017 Sep;17:623). This alteration was also reported in a proband whose endometrial and colorectal tumors demonstrated isolated of MSH6 staining on immunohistochemistry (IHC) and family history met Amsterdam II criteria for Lynch syndrome (Fokkema IF et al. Hum Mutat, 2011 May;32:557-63). In our internal cohort, this alteration has also been identified in an individual whose endometrial tumor demonstrated isolated loss of MSH6 staining on IHC and in individuals whose family histories met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data). This variant also demonstrated deficient mismatch repair activity in an in vitro complementation assay (Drost M et al. Genet Med, 2020 05;22:847-856). Based on internal structural assessment, this alteration destabilizes the fold of the ATPase domain (Warren JJ et al. Mol Cell, 2007 May;26:579-92). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471873	SCV000551224	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1211 of the MSH6 protein (p.Leu1211Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical feature of Lynch syndrome (PMID: 28874130; Invitae). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 219294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000215362	SCV001735479	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 1211 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro DNA mismatch repair assay found this variant protein to have nearly no activity compared to wildtype (PMID: 31965077). This variant has been observed in at least three individuals and a family affected with Lynch syndrome and/or Lynch syndrome-associated cancer with tumor histopathology consistent with DNA mismatch repair deficiency (PMID: 21520333, 28471861, 28874130; Leiden Open Variation Database Individual #00188773). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003454537	SCV004185563	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 [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003462359	SCV004198163	likely pathogenic	Endometrial carcinoma	2022-04-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477675	SCV004221235	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	The MSH6 c.3632T>C (p.Leu1211Pro) variant has been reported in the published literature in an affected family with Lynch Syndrome (PMID: 28874130 (2017)). An in vitro mismatch repair study demonstrated that this variant had no activity as compared to the wild type (PMID: 31965077 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000206750	SCV004848535	likely pathogenic	Lynch syndrome	2023-08-02	criteria provided, single submitter	clinical testing	The p.Leu1211Pro variant in MSH6 has been reported in at least 3 individuals with Lynch syndrome and segregated with disease in 2 affected relatives from 1 family (Rossi 2017 PMID: 28874130, de Paula 2021 PMID: 33647816, Libera 2016, Doctoral Thesis, Ambry pers. comm., Invitae pers. comm.). In addition, tumors sampled from 2 of these individuals showed either high microsatellite instability or lacked MSH6 expression. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as Pathogenic on June 21, 2019 by the ClinGen-approved International Society for Gastrointestinal Hereditary Tumors (InSiGHT) expert panel (ClinVar Variation ID 219294). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS3, PS4_Supporting, PM2_Supporting, PP3.