ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.725A>G (p.Asn242Ser) (rs779051492)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227866 SCV000284180 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 242 of the MSH2 protein (p.Asn242Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs779051492, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237404). 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: "Probably 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 RCV000235996 SCV000294055 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.725A>G at the cDNA level, p.Asn242Ser (N242S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has been observed in an individual with breast cancer (Yehia 2018). MSH2 Asn242Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Asn242Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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