ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1316C>T (p.Pro439Leu) (rs771789692)

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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 RCV000571303 SCV000669865 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000571303 SCV000684926 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780452 SCV000917708 uncertain significance not specified 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1316C>T (p.Pro439Leu) variant involves the alteration of a conserved nucleotide located in the DNA mismatch repair protein MutS, core (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 1/245806 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant was found in a DLBCL sample, though it was unknown whether it was germline or somatic in origin (de Miranda_2013). In addition, one clinical diagnostic laboratory classified this variant as one of uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV001067617 SCV001232685 uncertain significance Hereditary nonpolyposis colon cancer 2019-02-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 439 of the MSH2 protein (p.Pro439Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs771789692, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 483747). 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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