ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.728G>A (p.Arg243Gln) (rs63751455)

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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 RCV000131412 SCV000186388 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524419 SCV000254428 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 243 of the MSH2 protein (p.Arg243Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63751455, ExAC 0.009%). This variant has been reported in individuals affected with Lynch syndrome (PMID: 16395668, 21311894, 27468915). However, in three individuals, this variant occurs with two different pathogenic variants in MSH2 (PMID: 21311894, 27468915). While the data indicating the phase of these variants is not shown in detail in these papers, it is likely that the pathogenic variants and this variant are on the same chromosome. ClinVar contains an entry for this variant (Variation ID: 91189). This variant has been reported not to substantially affect MSH2 protein function (PMID: 30998989). 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.
Counsyl RCV000411200 SCV000488068 uncertain significance Lynch syndrome I 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000479306 SCV000565722 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.728G>A at the cDNA level, p.Arg243Gln (R243Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been observed in at least three individuals with colorectal cancer who met Amsterdam and/or Bethesda criteria; however two of them were also found to harbor a pathogenic MSH2 variant and a common haplotype (Moussa 2011, Ziada-Bouchaar 2016). While this variant has been identified in a pediatric patient with constitutional mismatch repair deficiency (CMMR-D), this patient was also found to be homozygous for a large PMS2 deletion (Bodo 2015). Additionally, MSH2 Arg243Gln was observed in an individual with an unspecified advanced cancer, undergoing multi-gene panel testing (Mandelker 2017). MSH2 Arg243Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Arg243Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131412 SCV000690126 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781566 SCV000919718 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246198 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728G>A has been reported in the literature in individuals affected with Lynch Syndrome without strong evidence for causality. Co-occurrences with other pathogenic MSH2 variants have been reported in the literature (c.1413dupA/p.P472TfsX4; c.1030C>T/p.Gln344X), providing supporting evidence for a benign role. Two publications report experimental evidence evaluating an impact on splicing, though neither provides convincing conclusions about the variant effect on protein function. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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