ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1911del (p.Arg638fs) (rs63750893)

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Total submissions: 5
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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 2018-07-22 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 2020-06-16 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Lynch syndrome (PMID: 17846840, 28874130). This variant is also known as c.1910delC in the literature. ClinVar contains an entry for this variant (Variation ID: 90816). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000201962 SCV000257158 likely pathogenic not provided no assertion criteria provided research

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