ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1153C>G (p.Pro385Ala) (rs763985746)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519754 SCV000618180 uncertain significance not provided 2017-03-14 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1153C>G at the cDNA level, p.Pro385Ala (P385A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro385Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Pro385Ala occurs at a position that is conserved across species and is located in the Lever domain and in a region known to interact with MSH6 and MSH3 (Guerrette 1998, Lützen 2008, Kansikas 2011) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Pro385Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000547472 SCV000625230 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 385 of the MSH2 protein (p.Pro385Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 449782). 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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