Submissions for variant NM_000179.3(MSH6):c.1571dup (p.Tyr524Ter)

dbSNP: rs1553412966

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000538459	SCV000624662	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr524*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome-associated tumors and/or polyps (PMID: 24100870, 25980754). ClinVar contains an entry for this variant (Variation ID: 433910). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657809	SCV000779564	pathogenic	not provided	2021-05-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Terui 2013, Yurgelun 2015, Ballinger 2016); This variant is associated with the following publications: (PMID: 25980754, 24100870, 27498913, 28323777)
Ambry Genetics	RCV001012235	SCV001172662	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	The c.1571dupA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of A at nucleotide position 1571, causing a translational frameshift with a predicted alternate stop codon (p.Y524*). This mutation has been reported in a Japanese individual with MSI-H colorectal cancer showing loss of MSH6 protein expression by immunohistochemistry (Terui H et al. Oncol. Rep., 2013 Dec;30:2909-16). This alteration was also identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797740	SCV002041500	pathogenic	Hereditary nonpolyposis colon cancer	2021-11-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1571dupA (p.Tyr524X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes and c.1571dupA has been reported in the literature in individuals affected with Lynch Syndrome (Roberts_2018, Terui_2013, Yurgelun_2015, Buchanan_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV003447536	SCV004175381	pathogenic	Lynch syndrome 5	2023-04-27	criteria provided, single submitter	clinical testing	The MSH6 c.1571dup variant is classified as Pathogenic (PVS1, PS4_Supporting, PM2, PP4) The MSH6 c.1571dup variant is a single nucleotide change which is predicted to cause a shift in the reading frame at codon 524, resulting in premature termination of the protein product. The variant has been reported in 2 unrelated individuals in the literature presenting with Lynch syndrome (PMID: 24100870, 25980754) and a patient with endometrial cancer (PMID:27398995) (PS4_Supporting) and is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH6 gene and this patient has loss of expression of MSH6 and MSH2 protein in tumour IHC staining (PP4). The variant has been reported in dbSNP (rs1553412966) and in the HGMD database as disease causing (CI1311629). It has been reported as pathogenic in the InSiGHT database (MSH6_000086) and by other diagnostic laboratories (ClinVar Variation ID: 433910).
Myriad Genetics, Inc.	RCV003447536	SCV004188281	pathogenic	Lynch syndrome 5	2023-08-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV004003519	SCV004841906	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant inserts a single nucleotide in exon 4 of the MSH6 gene, causing a frameshift and premature translational stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers and breast cancer (PMID: 24100870, 25980754, 29345684). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504411	SCV000592590	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Tyr524X variant was not identified in the literature but was seen in HGMD and “InSiGHT Colon Cancer Database”. InSiGHT and UMD (2x) have listed another variant (c.1572C>G) that results in the same amino acid change and lists this change as pathogenic or causal respectively. The p.Tyr524X variant leads to a premature stop codon at position 524, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.