ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2789dup (p.Val932fs) (rs786202481)

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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 RCV000165311 SCV000216033 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing The c.2789dupT variant, located in coding exon 16 of the MSH2 gene, results from a duplication of T at nucleotide position 2789, causing a translational frameshift with a predicted alternate stop codon (p.V932Sfs*21). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MSH2, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 17 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000198076 SCV000255274 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-15 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the last exon of MSH2 gene (p.Val932Serfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acids of the MSH2 protein and extend the length of the protein by 17 additional amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 185819). 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.
GeneDx RCV000236328 SCV000292856 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH2 is denoted c.2789dupT at the cDNA level and p.Val932SerfsX21 (V932SfsX21) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CGAA[dupT]AAAAG. The duplication causes a frameshift, which changes a Valine to a Serine at codon 932 in the last exon of the protein, and creates a stop codon at position 21 of the new reading frame. The last three amino acids are replaced by 20 incorrect ones, the clinical significance of which is unclear. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant occurs in the region of interaction with MSH6 and MSH3 and in the helix-turn-helix domain (Guerrette 1998, Lutzen 2008, Kansikas 2011). This variant has not to our knowledge, been published in the literature as pathogenic or benign. Based on the currently available information, we consider this duplication to be a variant of uncertain significance.
Color RCV000165311 SCV001358269 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-12 criteria provided, single submitter clinical testing

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