ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1827del (p.His610fs) (rs587779112)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491249 SCV000580540 pathogenic Hereditary cancer-predisposing syndrome 2017-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000076297 SCV000917695 likely pathogenic Lynch syndrome 2018-10-09 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1827delT (p.His610ThrfsX25) 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 and p.Arg680X). The variant was absent in 246248 control chromosomes. To our knowledge, no occurrence of c.1827delT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076297 SCV000107318 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000531842 SCV000625320 pathogenic Hereditary nonpolyposis colon cancer 2017-03-21 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 12 of the MSH2 mRNA (c.1827delT), causing a frameshift at codon 610. This creates a premature translational stop signal (p.His610Thrfs*25) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). It variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). For these reasons, this variant has been classified as Pathogenic.

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