Submissions for variant NM_000179.3(MSH6):c.3188T>G (p.Leu1063Arg)

dbSNP: rs1060502901

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000623149	SCV000740672	pathogenic	Lynch syndrome 1	2018-03-09	reviewed by expert panel	curation	Class 5 - Pathogenic Classification using multifactorial probability: 0.9978
Invitae	RCV002230108	SCV000551112	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1063 of the MSH6 protein (p.Leu1063Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 23733757, 26099011, 28531214, 33693762; Invitae). ClinVar contains an entry for this variant (Variation ID: 410436). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this missense change affects MSH6 function (PMID: 24362816, 28531214, 31965077). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491375	SCV000580251	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-16	criteria provided, single submitter	clinical testing	The p.L1063R variant (also known as c.3188T>G), located in coding exon 5 of the MSH6 gene, results from a T to G substitution at nucleotide position 3188. The leucine at codon 1063 is replaced by arginine, an amino acid with dissimilar properties. The p.L1063R alteration has been reported in multiple individuals whose Lynch syndrome-associated tumor showed MSH6 loss on IHC (Ward RL et al. J Clin Oncol. 2013 Jul 10;31(20):2554-62; Graham RP et al. Am. J. Surg. Pathol., 2015 Oct;39:1370-6; Ambry internal data). In a functional study, the equivalent allele in mice (p.L1060R) demonstrated resistance to DNA damaging agents, reduced protein expression, and increased microsatellite instability similar to known pathogenic variants which were used in the validation of the study (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000491375	SCV002052247	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1063 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). Functional studies have shown that this variant retained less than 20% of mismatch repair activity compared to wild type MSH6 protein (PMID: 28531214, 31965077). This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated tumors (PMID: 23733757, 33693762; ClinVar SCV000551112.4, SCV000580251.5). Several of these individuals had tumors that displayed loss of MSH2 and/or MSH6 protein via immunohistochemistry analysis. 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 Pathogenic.
GeneDx	RCV002051855	SCV002318998	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced mismatch repair activity and reduced protein expression (Houlleberghs 2017, Drost 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26099011, 23733757, 31965077, 28531214, 17531815, 21120944, 33693762, 34445333)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272245	SCV002557423	pathogenic	Lynch syndrome 5	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary nonpolyposis colorectal cancer. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MutS III domain (Decipher). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Leu1063Val) variant has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). This variant has also been identified in five colorectal cancer patients (PMIDs: 23733757, 26099011, VCGS Lynch syndrome cohort). ClinVar contains conflicting interpretations of pathogenicity, pathogenic, likely pathogenic and VUS. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been functionally shown to reduced protein expression and increased microsatellite instability to a similar amount to known pathogenic variants (PMID: 28531214). Microsatellite instability has been observed in patients with this variant (PMID: 26099011). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Myriad Genetics, Inc.	RCV002272245	SCV004185554	likely pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28531214]. This variant is expected to disrupt protein structure [Myriad internal data].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002051855	SCV004221211	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 23733757 (2013), 26099011 (2015)) and endometrial cancer (PMID: 33693762 (2021)). Functional studies of this variant have observed reduction or loss of protein expression and defective mismatch repair activity (PMID: 23733757 (2013), 28531214 (2017)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV004001829	SCV004837235	pathogenic	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1063 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). Functional studies have shown that the mutant is defective in DNA mismatch repair in cell-free in vitro assay (PMID: 31965077) and as measured indirectly by resistance to 6-thioguanine in mouse embryonic stem cells (PMID: 28531214). This variant has been observed in individuals affected with colorectal cancer, whose tumors showed loss of MSH6 expression by immunohistochemistry (PMID: 23733757, 26099011). In one family, this variant showed segregation with disease with likelihood ratio of 9.67 (InSiGHT database, http://insight-database.org/). 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.