Submissions for variant NM_000179.3(MSH6):c.2300C>T (p.Thr767Ile)

dbSNP: rs587781462

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000622945	SCV000740675	pathogenic	Lynch syndrome 1	2018-03-09	reviewed by expert panel	curation	Class 5 - Pathogenic Classification using multifactorial probability: 0.993
Ambry Genetics	RCV000129397	SCV000184163	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The p.T767I pathogenic mutation (also known as c.2300C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2300. The threonine at codon 767 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in several individuals whose Lynch-related tumors demonstrated high microsatellite instability and/or demonstrated loss of MSH6 expression on immunohistochemistry (IHC) and family history meets Amsterdam criteria (Ambry internal data; Fokkema IF et al. Hum. Mutat., 2011 May;32:557-63; Stembalska A et al. Eur. J. Obstet. Gynecol. Reprod. Biol., 2019 Jul;238:54-57). This alteration is also present in five first degree female relatives diagnosed with endometrial cancer (Stembalska A et al. Eur. J. Obstet. Gynecol. Reprod. Biol., 2019 Jul;238:54-57). In one in vitro complementation assay, mismatch repair activity for this variant was similar to that of the pathogenic control (Drost M et al. Genet Med, 2020 05;22:847-856). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000410431	SCV000488090	uncertain significance	Lynch syndrome 5	2015-12-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477388	SCV000551179	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 767 of the MSH6 protein (p.Thr767Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 29755653, 31100584). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 141058). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH6 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000501569	SCV000601529	uncertain significance	not specified	2017-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251301	SCV001426843	pathogenic	Hereditary nonpolyposis colon cancer	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2300C>T (p.Thr767Ile) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251156 control chromosomes (gnomAD). c.2300C>T has been reported in the literature in individuals affected with endometrial cancer (example: Adar_2018, Stembalska_2019, and Lawrence_2021). In one family, this variant has been reported to segregate with the disease (Stembalska_2019). These data indicate that the variant is very likely to be associated with disease. In functional in vitro studies, the variant was found to have reduced mismatch repair (MMR) activity (Drost_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000129397	SCV002535720	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410431	SCV004185574	likely pathogenic	Lynch syndrome 5	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function. This variant is expected to disrupt protein structure [Myriad internal data].
Color Diagnostics, LLC DBA Color Health	RCV000129397	SCV004357642	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 767 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). A functional study has shown that this variant results in a significant decrease in mismatch repair activity compared to wild type MSH6 protein (PMID: 31965077). This variant has been reported in individuals affected with endometrial, uterine, and colorectal cancers (PMID: 29755653, 31100584, 33467402; ClinVar SCV000184163.7), and it has been shown that this variant segregates with disease in one family (PMID: 31100584). 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	RCV004719708	SCV005326058	likely pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate reduced in vitro mismatch repair activity compared to wild type (PMID: 31965077); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28153049, 21520333, 33372952, 17531815, 21120944, 31100584, 29755653, 33281875, 33467402, 30128536, 31965077, 29750335)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353758	SCV000592603	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Thr767Ile variant was identified in the literature found in patient with clear cell carcinoma of the uterus and absence of MSH6 protein and presence of protein for MLH1, MSH2 and PMS2 on IHC (Gray 2018), found in patient in second recurrence heterogeneously enhancing infiltrating tumor (Erson-Omay 2017) and in an endometrial cancer patient with isolated loss of MSH6 in tumour (McGill University Health Centre personal communication). In addition, the variant was identified in our laboratory in one family with segregation in 3 individuals. The variant was also identified in dbSNP (ID: rs587781462) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by InSight; as likely pathogenic by Ambry Genetics; as uncertain significance by Invitae, Counsyl and COGR). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Thr767 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257543	SCV001434369	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation