ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1861C>T (p.Arg621Ter) (rs63750508)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076305 SCV000107327 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000524364 SCV000260744 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg621*) 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 several families affected with Lynch syndrome and colorectal cancer (PMID: 8566964, 12624141, 17569143, 18772310, 20007843, 21598002, 21642682, 24415873). ClinVar contains an entry for this variant (Variation ID: 90804). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000414448 SCV000490618 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.1861C>T at the cDNA level and p.Arg621Ter (R621X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 Arg621Ter has been reported in multiple individuals with personal/family history consistent with Lynch syndrome (Maliaka 1996, Zavodna 2006, van Puijenbroek 2008, Vierkoetter 2014, Sunga 2017) and is considered pathogenic.
Ambry Genetics RCV000491286 SCV000580383 pathogenic Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000414448 SCV000601443 pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing
Color RCV000491286 SCV000684988 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076305 SCV000696226 pathogenic Lynch syndrome 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1861C>T (p.Arg621X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, ESP, or 1000 Gs) and multiple publications have cited the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/databases cite the variant with a classification of "Pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000602838 SCV000744278 pathogenic Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763492 SCV000894278 pathogenic Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000602838 SCV000734202 pathogenic Lynch syndrome I no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249915 SCV001423932 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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