ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2680dup (p.Met894fs) (rs876658211)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214664 SCV000273149 pathogenic Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000214664 SCV000908332 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000657245 SCV000778975 likely pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH2 is denoted c.2680dupA at the cDNA level and p.Met894AsnfsX5 (M894NfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACAA[dupA]TGCC. The duplication causes a frameshift which changes a Methionine to an Asparagine at codon 894, 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 protein truncation. MSH2 c.2680dupA has been reported in individuals with Lynch syndrome, and mismatch repair immunohistochemistry (MMR IHC) data available on a tumor showed loss of MSH2 and MSH6 in at least one carrier (Casey 2005, Lagerstedt-Robinson 2016). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Invitae RCV000810344 SCV000950540 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Met894Asnfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the MSH2 protein. This variant is present in population databases (rs756190190, ExAC 0.005%). This variant has been observed in several individuals affected with colorectal cancer (PMID: 15713769, 27601186, 28514183). This variant is also known as 2680_2681insA, M896Xfs in the literature. ClinVar contains an entry for this variant (Variation ID: 229809). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000614715 SCV000731411 uncertain significance not specified 2017-03-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met894fs variant in MSH2 has been reported in 1 individual with colorectal cancer that ha d a loss of MSH2 and MSH6 expression in their tumor (Casey 2005). This variant h as also been identified in 3/65500 of European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs876658211). The p .Met894fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 894 and leads to a premature terminat ion codon 5 amino acids downstream. This termination codon occurs within the las t exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function pathogenic variants in the last exon of MS H2 have been reported in individuals with Lynch Syndrome. In summary, while ther e is some suspicion for a pathogenic role, the clinical significance of the p.Me t894fs variant is uncertain.

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