ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.646A>T (p.Ile216Leu)

dbSNP: rs63749936
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000774471 SCV000908174 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-16 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 216 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). To our knowledge, 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.
All of Us Research Program, National Institutes of Health RCV004001404 SCV004830905 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 216 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). To our knowledge, 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.
Ambry Genetics RCV000774471 SCV005033719 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-10 criteria provided, single submitter clinical testing The p.I216L variant (also known as c.646A>T) is located in coding exon 4 of the MSH2 gene. The isoleucine at codon 216 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 4. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This nucleotide position is not well conserved in available vertebrate species. This amino acid position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. In addition, as a missense substitution in silico analysis is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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