Submissions for variant NM_000251.3(MSH2):c.1911del (p.Arg638fs)

dbSNP: rs63750893

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076318	SCV000107341	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000201962	SCV000568632	pathogenic	not provided	2018-02-13	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH2 is denoted c.1911delC at the cDNA level and p.Arg638GlyfsX47 (R638GfsX47) at the protein level. The normal sequence, with the base that is deleted in brackets, is CATC[delC]AGGC. The deletion causes a frameshift which changes an Arginine to a Glycine at codon 638, and creates a premature stop codon at position 47 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.1911delC, also published as MSH2 c.1910delC, has been reported in at least one family meeting Amsterdam criteria with colorectal, endometrial and additional cancers (Vaccaro 2007, Dominguez-Valentin 2016). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491809	SCV000580550	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-13	criteria provided, single submitter	clinical testing	The c.1911delC pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1911, causing a translational frameshift with a predicted alternate stop codon (p.R638Gfs*47). This mutation (designated 1910delC) was detected in an Argentinean family meeting Amsterdam II criteria, in which the proband was affected with cancers of the cecum, endometrium, duodenum, and breast. Testing revealed high microsatellite instability and absence of MSH2 expression on IHC in the colon, duodenum, and breast tumors (Vaccaro CA et al. Dis. Colon Rectum 2007 Oct;50:1604-11). 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.
Invitae	RCV000818764	SCV000959395	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg638Glyfs*47) 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 (PMID: 17846840, 28874130). This variant is also known as c.1910delC. ClinVar contains an entry for this variant (Variation ID: 90816). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491809	SCV002053407	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a family affected with Lynch syndrome (PMID: 17846840, 24344984, 28127413, 28874130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452868	SCV004188082	pathogenic	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201962	SCV000257158	likely pathogenic	not provided		no assertion criteria provided	research