ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.2176A>C (p.Ile726Leu)

gnomAD frequency: 0.00005  dbSNP: rs752400305
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000794695 SCV000934120 uncertain significance not provided 2024-12-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 726 of the MSH3 protein (p.Ile726Leu). This variant is present in population databases (rs752400305, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 641451). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics RCV001014638 SCV001175371 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-14 criteria provided, single submitter clinical testing The p.I726L variant (also known as c.2176A>C), located in coding exon 15 of the MSH3 gene, results from an A to C substitution at nucleotide position 2176. The isoleucine at codon 726 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in an individual with colorectal cancer as well as non-cancer control individuals (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV001014638 SCV002536040 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-06 criteria provided, single submitter curation
Baylor Genetics RCV003461081 SCV004196983 uncertain significance Endometrial carcinoma 2024-01-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005047062 SCV005666198 uncertain significance Endometrial carcinoma; Familial adenomatous polyposis 4 2024-01-22 criteria provided, single submitter clinical testing

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