ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1814T>C (p.Val605Ala) (rs1064794881)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482213 SCV000570145 uncertain significance not provided 2016-04-27 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1814T>C at the cDNA level, p.Val605Ala (V605A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val605Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val605Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in Lever domain as well as the region of interaction with EXO1 (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Val605Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580848 SCV000684980 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Invitae RCV001225204 SCV001397445 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-03 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 605 of the MSH2 protein (p.Val605Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine 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 conditions. ClinVar contains an entry for this variant (Variation ID: 421059). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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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