ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2684C>G (p.Pro895Arg) (rs786203553)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166913 SCV000217732 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000484021 SCV000567870 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2684C>G at the cDNA level, p.Pro895Arg (P895R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro895Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro895Arg occurs at a position that is not conserved and is located in the Helix-turn-helix domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Pro895Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001058479 SCV001223054 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-26 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 895 of the MSH2 protein (p.Pro895Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187208). 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 tolerated, 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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