ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1817T>A (p.Val606Asp)

gnomAD frequency: 0.00002  dbSNP: rs376044376
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129574 SCV000184356 uncertain significance Hereditary cancer-predisposing syndrome 2021-03-25 criteria provided, single submitter clinical testing The p.V606D variant (also known as c.1817T>A), located in coding exon 12 of the MSH2 gene, results from a T to A substitution at nucleotide position 1817. The valine at codon 606 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000473039 SCV000548198 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-12-31 criteria provided, single submitter clinical testing 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 141180). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (rs376044376, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 606 of the MSH2 protein (p.Val606Asp).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003137636 SCV003807159 uncertain significance Lynch syndrome 1 2023-02-10 criteria provided, single submitter clinical testing ACMG classification criteria: PM2 supporting, PP3 supporting
Baylor Genetics RCV003137636 SCV004196288 uncertain significance Lynch syndrome 1 2023-08-24 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997511 SCV004827411 uncertain significance Lynch syndrome 2023-07-10 criteria provided, single submitter clinical testing This missense variant replaces valine with aspartic acid at codon 606 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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