ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2417C>T (p.Thr806Ile)

dbSNP: rs758889557
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205485 SCV000259450 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000480146 SCV000566944 uncertain significance not provided 2020-06-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with colorectal cancer whose tumor demonstrated high microsatellite instability, lacked PMS2 expression, and harbored two somatic MLH1 variants (Pearlman 2019); This variant is associated with the following publications: (PMID: 30877237)
Ambry Genetics RCV000568311 SCV000662317 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-21 criteria provided, single submitter clinical testing The p.T806I variant (also known as c.2417C>T), located in coding exon 14 of the MSH2 gene, results from a C to T substitution at nucleotide position 2417. The threonine at codon 806 is replaced by isoleucine, an amino acid with similar properties. 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 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000568311 SCV000685040 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 806 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251392 chromosomes 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.
Mendelics RCV000708843 SCV000837852 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000568311 SCV002534473 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-04 criteria provided, single submitter curation

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