ClinVar Miner

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

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Total submissions: 6
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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 2020-09-11 criteria provided, single submitter clinical testing The c.2680dupA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a duplication of one nucleotide at position c.2680 resulting in a translational frameshift with a predicted alternate stop codon (p.M894Nfs*5). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in multiple individuals diagnosed with colorectal cancer that demonstrated either high microsatellite instability (MSI-H) or absent MSH2 and/or MSH6 staining by immunohistochemistry (IHC) (Ambry internal data; Casey G et al. JAMA 2005 Feb; 293(7):799-809). As such, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000614715 SCV000731411 likely pathogenic Lynch syndrome 2020-02-07 criteria provided, single submitter clinical testing The p.Met894AsnfsX5 variant in MSH2 has been reported in at least 2 individuals with Lynch syndrome associated cancers (Casey 2005, Lagerstedt-Robinson 2016, Carter 2018). In addition, tumors sampled from 1 of these individuals lacked MSH2 and MSH6 expression. This variant has also been identified in 3/113586 of European chromosomes by gnomAD ( This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2, PS4_Supporting, PS3_Moderate.
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.
Color Health, Inc RCV000214664 SCV000908332 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Invitae RCV000810344 SCV000950540 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-04-09 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000657245 SCV001449568 pathogenic not provided 2014-09-10 criteria provided, single submitter clinical testing

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