Submissions for variant NM_000251.3(MSH2):c.187del (p.Gly62_Val63insTer)

dbSNP: rs63750160

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076310	SCV000107331	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000202123	SCV000293285	pathogenic	not provided	2018-09-18	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted MSH2 c.187delG at the cDNA level and p.Val63Ter (V63X) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGGGG[delG]TGAT. The deletion creates a nonsense variant, which changes a Valine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). MSH2 c.187delG has been identified in individuals with a personal and family history suggestive of Lynch syndrome, and tumors from several of these individuals exhibited microsatellite instability and/or absence of MSH2 expression (Beherns 2003, Mangold 2005, Lotsari 2012). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491017	SCV000580445	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The c.187delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 187, causing a translational frameshift with a predicted alternate stop codon (p.V63*). This mutation has been reported in multiple HNPCC/Lynch syndrome patients; several whose tumors demonstrated loss of MSH2 staining by immunohistochemistry (IHC) (Behrens P et al. Int. J. Cancer, 2003 Nov;107:183-8; Mangold E et al. J Pathol, 2005 Dec;207:385-95; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). This mutation was also identified in an individual diagnosed with breast cancer at age 55, whose breast tumor showed microsatellite instability and absent MSH2 and MSH6 staining on IHC (Lotsari JE et al. Breast Cancer Res. 2012 Jun 12;14(3):R90). 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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000076310	SCV000914296	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Invitae	RCV001231661	SCV001404190	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-09-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90808). This premature translational stop signal has been observed in individual(s) with breast cancer and Lynch syndrome (PMID: 15849733, 22691310, 26437257, 27601186). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val63*) 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).
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202123	SCV001449969	pathogenic	not provided	2019-10-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452865	SCV004188132	pathogenic	Lynch syndrome 1	2023-07-26	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202123	SCV000257156	pathogenic	not provided		no assertion criteria provided	research