ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1984C>T (p.Gln662Ter)

dbSNP: rs786204321
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480108 SCV000568633 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1984C>T at the cDNA level and p.Gln662Ter (Q662X) 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 2 families suspicious for Lynch syndrome (Parc 2003, Bonadona 2011), and is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192611 SCV001360854 likely pathogenic Hereditary nonpolyposis colon cancer 2019-01-04 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1984C>T (p.Gln662X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Arg680X, p.Gln681X, p.Val705fsX5). The variant was absent in 276630 control chromosomes. c.1984C>T has been reported in the literature in individuals affected with Lynch Syndrome (Bonadona_2011, Parc_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001239760 SCV001412657 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-01-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln662*) 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 clinical features of Lynch syndrome (PMID: 12624141, 21642682, 30521064). ClinVar contains an entry for this variant (Variation ID: 188516). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002415717 SCV002717887 pathogenic Hereditary cancer-predisposing syndrome 2020-09-21 criteria provided, single submitter clinical testing The p.Q662* variant (also known as c.1984C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1984. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been reported in multiple cohorts with features consistent with Lynch syndrome (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Roberts ME et al. Genet. Med., 2018 10;20:1167-1174; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int. J. Cancer, 2019 05;144:2161-2168). 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.
Myriad Genetics, Inc. RCV003454427 SCV004188175 pathogenic Lynch syndrome 1 2023-08-04 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000168729 SCV000592526 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH2, p.Gln662X variant was identified in 2 of 1946 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Bonadona 2011, Parc 2003). The variant was also identified in HGMD, GeneInsight VariantWire database (1X, classified as “IARC 5” by a clinical laboratory) and UMD (2X as a causal variant). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln662X variant leads to a premature stop codon at position 662, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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