Submissions for variant NM_000179.3(MSH6):c.2906A>G (p.Tyr969Cys)

dbSNP: rs63749919

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000623975	SCV000740676	likely pathogenic	Lynch syndrome 1	2018-03-09	reviewed by expert panel	curation	Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.9528
GeneDx	RCV000218181	SCV000279613	likely pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 16813607, 23621914, 19723918, 20587412, 29922827, 36988593, 30536544, 34178123, 34667028, Basel-Salmon2023[CaseReport], 34172528)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458194	SCV000551056	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 969 of the MSH6 protein (p.Tyr969Cys). This variant is present in population databases (rs63749919, gnomAD 0.003%). This missense change has been observed in individuals with Lynch syndrome (PMID: 16813607, 19723918, 20587412). 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: 234622). 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%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491101	SCV000580279	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-07-15	criteria provided, single submitter	clinical testing	The p.Y969C variant (also known as c.2906A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2906. The tyrosine at codon 969 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (Grindedal EM et al. Cancer Epidemiol. Biomarkers Prev. 2009 Sep;18(9):2460-7; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (Suchy J et al. Clin Genet. 2006 Jul;70(1):68-70; Ambry internal data). This variant has also been reported in an individual from a cohort of adult optic glioma patients (Sa JK et al. Int. J. Cancer. 2019 06;144:3023-3030). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467444	SCV002762824	likely pathogenic	Lynch syndrome 5	2022-12-09	criteria provided, single submitter	research	PS4_STR, PM5, PP1
Revvity Omics, Revvity	RCV000218181	SCV003833165	likely pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002467444	SCV004189278	likely pathogenic	Lynch syndrome 5	2023-08-21	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]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16813607,19723918, 20587412].
Baylor Genetics	RCV003463615	SCV004198136	likely pathogenic	Endometrial carcinoma	2022-08-13	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003165582	SCV002758545	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research