ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2113del (p.Val705fs) (rs63749811)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030250 SCV000107421 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Integrated Genetics/Laboratory Corporation of America RCV001175339 SCV000052917 pathogenic Hereditary nonpolyposis colon cancer 2019-07-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2113delG (p.Val705TrpfsX5) 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 251476 control chromosomes. c.2113delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Lin_1999, Hegde_2005, Nilbert_2009, Coolbaugh-Murphy_2010). 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.
Ambry Genetics RCV000223638 SCV000278375 pathogenic Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000791368 SCV000548168 pathogenic Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val705Trpfs*5) 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 to segregate with Lynch syndrome-related cancers in several families (PMID: 8723682). In addition, this variant has been observed in unrelated individuals affected with Lynch syndrome (PMID: 18566915, 20052760, 8872463). ClinVar contains an entry for this variant (Variation ID: 1760). 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 RCV000482957 SCV000568634 pathogenic not provided 2017-08-04 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.2113delG at the cDNA level and p.Val705TrpfsX5 (V705WfsX5) at the protein level. The normal sequence, with the base that is deleted in braces, is CATT[G]TGGA. The deletion causes a frameshift which changes a Valine to a Tryptophan at codon 705, and creates a premature stop codon at position 5 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.2113delG has been reported in families who meet Amsterdam criteria for Lynch syndrome and families suspicious for Lynch syndrome (Jeon 1996, Moslein 1996, Lin 1999, Domingo 2004, Hegde 2005, Nilbert 2009, Coolbaugh-Murphy 2010). Based on currently available evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482957 SCV000601455 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
Color RCV000223638 SCV001347251 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
OMIM RCV000001830 SCV000021986 pathogenic Lynch syndrome I 1996-01-01 no assertion criteria provided literature only

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