ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1862G>A (p.Arg621Gln)

gnomAD frequency: 0.00001  dbSNP: rs759263820
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Total submissions: 7
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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 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 621 of the MSH2 protein (p.Arg621Gln). This variant is present in population databases (rs759263820, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141). ClinVar contains an entry for this variant (Variation ID: 455528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function with a positive predictive value of 80%. 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: 21520333, 30702970; 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 2023-12-07 criteria provided, single submitter clinical testing The p.R621Q variant (also known as c.1862G>A), located in coding exon 12 of the MSH2 gene, results from a G to A substitution at nucleotide position 1862. The arginine at codon 621 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a cohort of 348 French subjects from 163 families who met at least one of the modified Amsterdam criteria, and authors classified this alteration as non-functional (likely to be a polymorphism) (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000663143 SCV000786290 uncertain significance Lynch syndrome 1 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.
GeneDx RCV001764525 SCV001990759 uncertain significance not provided 2019-12-17 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29887214, 12624141)
Myriad Genetics, Inc. RCV000663143 SCV004018217 uncertain significance Lynch syndrome 1 2023-03-16 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
University of Washington Department of Laboratory Medicine, University of Washington RCV000663143 SCV001446386 likely pathogenic Lynch syndrome 1 2018-07-11 no assertion criteria provided clinical testing

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