ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.80C>T (p.Pro27Leu) (rs750746034)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164692 SCV000215359 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000228123 SCV000284189 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 27 of the MSH2 protein (p.Pro27Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs750746034, ExAC 0.02%). This variant has been reported in an individual affected with colorectal cancer. However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.80C>T variant was not the primary cause of disease. (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 185297). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000235224 SCV000292613 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.80C>T at the cDNA level, p.Pro27Leu (P27L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has been reported in an individual with early onset mismatch repair (MMR) deficient colon cancer; however, this individual was also found to harbor a frameshift variant in MLH1 which could explain the observed MMR deficiency (Pearlman 2017). MSH2 Pro27Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Pro27Leu is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH2 Pro27Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000412025 SCV000489554 uncertain significance Lynch syndrome I 2016-10-21 criteria provided, single submitter clinical testing
Color RCV000164692 SCV000685130 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Mendelics RCV000708825 SCV000837812 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235224 SCV001134375 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing

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