ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.687del (p.Ala230fs) (rs63749897)

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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) RCV000076681 SCV000107716 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524417 SCV000548211 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala230Leufs*16) 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 reported in individuals and families with Lynch syndrome (PMID: 10480359, 15926618, 15849733, 10404063). It is also known as a 1bp deletion at codons 227-229 in the literature. ClinVar contains an entry for this variant (Variation ID: 91177). 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 RCV000202204 SCV000568622 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.687delA at the cDNA level and p.Ala230LeufsX16 (A230LfsX16) at the protein level. The normal sequence, with the base that is deleted in braces, is GAAAAAA[A]GCTG. The deletion causes a frameshift which changes an Alanine to a Leucine at codon 230, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.687delA has been reported in association with Lynch syndrome and is considered to be pathogenic (Mangold 2005, Wolf 2005, Batte 2014).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076681 SCV000592476 pathogenic Lynch syndrome 2016-08-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV001025755 SCV001188005 pathogenic Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV001175575 SCV001339208 pathogenic Hereditary nonpolyposis colon cancer 2020-03-27 criteria provided, single submitter clinical testing Variant summary: MSH2 c.687delA (p.Ala230LeufsX16) 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. The variant was absent in 251224 control chromosomes. c.687delA has been reported in the literature in multiple individuals affected with Hereditary Non-Polyposis Colon Cancer (eg. Jiang_2019, Mangold_2005, Wang_1999, Wolf_2005, Bai_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202204 SCV000257194 pathogenic not provided no assertion criteria provided research

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