ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.14C>T (p.Pro5Leu) (rs56170584)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160589 SCV000211184 uncertain significance not provided 2016-03-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.14C>T at the cDNA level, p.Pro5Leu (P5L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro5Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Pro5Leu occurs at a position that is conserved across species and is located in the mismatch binding domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Pro5Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000559215 SCV000625274 uncertain significance Hereditary nonpolyposis colon cancer 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 5 of the MSH2 protein (p.Pro5Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs56170584, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182561). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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