Submissions for variant NM_000251.2(MSH2):c.508C>T (p.Gln170Ter) (rs63750843)

Total submissions: 6

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	2019-06-24	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. This variant is not present in population databases (ExAC no frequency). This particular variant has been reported in the literature in individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 15849733, 17348456, 24710284, 20215533, 26485756). ClinVar contains an entry for this variant (Variation ID: 91117). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491287	SCV000580397	pathogenic	Hereditary cancer-predisposing syndrome	2018-12-31	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
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785436	SCV000924008	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research