ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1838dup (p.Asn613fs) (rs1114167815)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491996 SCV000580453 pathogenic Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing The c.1838dupA pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a duplication of A at nucleotide position 1838, causing a translational frameshift with a predicted alternate stop codon (p.N613Kfs*31). This pathogenic mutation has been reported in one HNPCC family that had a strong history of ureter, bladder, and kidney cancers (Geary J et al. Fam Cancer. 2008;7(2):163-72). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781568 SCV000919720 likely pathogenic Lynch syndrome 2018-11-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1838dupA (p.Asn613LysfsX31) 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 (e.g. p.Arg621X, p.Arg680X, p.Gln681X). The variant was absent in 246258 control chromosomes (gnomAD). The variant, c.1838dupA, has been reported in the literature in a family affected with Lynch Syndrome (Geary 2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001380770 SCV001578928 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn613Lysfs*31) 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 individual(s) with clinical features of Lynch syndrome (PMID: 17939062). ClinVar contains an entry for this variant (Variation ID: 428465). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.

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