ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.643C>T (p.Gln215Ter)

dbSNP: rs63751274
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076658 SCV000107693 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000657646 SCV000779392 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.643C>T at the cDNA level and p.Gln215Ter (Q215X) 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 at least one family with a history suggestive of Lynch syndrome (Bapat 1999), and is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001854334 SCV002233209 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-06-27 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: 91154). This premature translational stop signal has been observed in individual(s) with colorectal cancer and ovarian cancer (PMID: 10190329, 30322717). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln215*) 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).
Ambry Genetics RCV002362713 SCV002656780 pathogenic Hereditary cancer-predisposing syndrome 2024-05-09 criteria provided, single submitter clinical testing The p.Q215* variant (also known as c.643C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 643. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been reported in a patient diagnosed with a MSI-H early-onset colon cancer whose family history meets Amsterdam II criteria, as well as, in a patient diagnosed with a mismatch repair-deficient (MMRd) colorectal cancer and in a MMRd endometrial tumor cell line (Boyer JC et al. Cancer Res., 1995 Dec;55:6063-70; Bapat BV et al. Hum. Genet., 1999 Feb;104:167-76; Baert-Desurmont S et al. Eur. J. Hum. Genet., 2018 11;26:1597-1602). 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.
Human Genetics Bochum, Ruhr University Bochum RCV002463636 SCV002758604 pathogenic Lynch syndrome 1 2022-02-10 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PVS1, PS4, PM2
Johns Hopkins Genomics, Johns Hopkins University RCV003150809 SCV003839083 pathogenic Mismatch repair cancer syndrome 2 2023-01-03 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002463636 SCV004188993 pathogenic Lynch syndrome 1 2023-07-27 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.

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