ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1937A>C (p.Asp646Ala) (rs41295290)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228698 SCV000284126 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 646 of the MSH2 protein (p.Asp646Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs41295290, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237377). 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: "Benign"; Align-GVGD: "Class C65"). 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 RCV000483596 SCV000567864 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1937A>C at the cDNA level, p.Asp646Ala (D646A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp646Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Asp646Ala occurs at a position that is conserved in mammals and is located in the region of interaction with EXO1 and the ATPase domain (Lutzen 2008, Kansikas 2011). 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 Asp646Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575069 SCV000669760 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-15 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000575069 SCV000908320 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing

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