Submissions for variant NM_000251.3(MSH2):c.508C>T (p.Gln170Ter)

dbSNP: rs63750843

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076621	SCV000107656	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000236121	SCV000292617	pathogenic	not provided	2016-09-21	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.508C>T at the cDNA level and p.Gln170Ter (Q170X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with a personal and family history consistent with Lynch syndrome and is considered pathogenic (Mangold 2005, Irmejs 2007, Walsh 2010, Liu 2014).
Invitae	RCV000791416	SCV000548130	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln170*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 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 or Lynch syndrome-associated cancers (PMID: 15849733, 17348456, 20215533, 24710284, 26485756). ClinVar contains an entry for this variant (Variation ID: 91117). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491287	SCV000580397	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-05	criteria provided, single submitter	clinical testing	The p.Q170* pathogenic mutation (also known as c.508C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 508. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This alteration has been described in a German individual with HNPCC/Lynch syndrome based on modified Bethesda criteria and in a Latvian individual with suspected HNPCC/Lynch syndrome (Mangold E et al. Int J Cancer. 2005;116(5):692-702; Irmejs A et al. Anticancer Res. 2007;27(1):653-8). This mutation was also described in a female diagnosed with both breast and colon cancer; both of these tumors showed absent staining for MSH2 and MSH6 on IHC (Walsh MD et al. Clin Cancer Res. 2010;16:2214-2224). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236121	SCV000889443	pathogenic	not provided	2017-09-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH2 protein synthesis. 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 with colorectal cancer (PMID: 26485756 (2015), Lynch Syndrome (PMID: 24710284 (2014), 20215533 (2010), 17348456 (2007), 15849733 (2005)), and sarcoma (PMID: 29625052 (2018)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003452945	SCV004188153	pathogenic	Lynch syndrome 1	2023-07-27	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785436	SCV000924008	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236121	SCV001553610	uncertain significance	not provided		no assertion criteria provided	clinical testing