ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.797C>T (p.Ala266Val) (rs587781745)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129950 SCV000184773 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212590 SCV000211167 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.797C>T at the cDNA level, p.Ala266Val (A266V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has been observed in at least two individuals suspected of having Lynch syndrome due to personal and/or family history (Goldberg 2014, Yurgelun 2015). MSH2 Ala266Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ala266Val occurs at a position that is conserved across species and is located in the Connector domain (Lutzen 2008). 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 Ala266Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000630072 SCV000751028 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 266 of the MSH2 protein (p.Ala266Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25430799, 25980754). ClinVar contains an entry for this variant (Variation ID: 141437). 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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