ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1862G>A (p.Arg621Gln) (rs759263820)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549787 SCV000625323 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 621 of the MSH2 protein (p.Arg621Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs759263820, ExAC 0.02%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141). ClinVar contains an entry for this variant (Variation ID: 455528). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg621 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30702970, 21520333, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV000575117 SCV000669880 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000663143 SCV000786290 uncertain significance Lynch syndrome I 2018-04-10 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000758651 SCV000887414 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1862G>A has a 86.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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