ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.116G>C (p.Arg39Pro) (rs587782759)

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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 RCV000132280 SCV000187364 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000132280 SCV000908268 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780435 SCV000917683 uncertain significance not specified 2018-01-24 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.116G>C (p.Arg39Pro) variant involves the alteration of a conserved nucleotide that leads to an amino acid substitution in the N-terminal mismatch-recognition domain (IPR007695, InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/222394 control chromosomes at a frequency of 0.0000225, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant was reported in one individual with colorectal cancer, however without evidence for causality (Yurgelun 2017). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000800194 SCV000939894 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 39 of the MSH2 protein (p.Arg39Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs587782759, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142842). 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. 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.

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