ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2175C>G (p.Ile725Met) (rs63750304)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410569 SCV000488837 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-06-29 criteria provided, single submitter clinical testing
Invitae RCV000556059 SCV000624731 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 725 of the MSH6 protein (p.Ile725Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs63750304, ExAC 0.005%). This variant has been reported in an individual affected with colorectal cancer (PMID: 11709755). ClinVar contains an entry for this variant (Variation ID: 89257). An algorithm developed specifically for the MSH6 gene (PMID: 22290698, 23621914), suggests that this missense change is likely to be tolerated. However, this prediction has not been confirmed by published functional studies and its 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.
Ambry Genetics RCV000565677 SCV000662560 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-22 criteria provided, single submitter clinical testing The p.I725M variant (also known as c.2175C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2175. The isoleucine at codon 725 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in an individual diagnosed with colon cancer at 36, whose tumor showed presence of the MLH1, MSH2, and MSH6 proteins on immunohistochemistry, low microsatellite instability, and absence of the BRAF V600E mutation (Berends MJ et al. Am. J. Hum. Genet., 2002 Jan;70:26-37; Domingo E et al. Oncogene, 2005 Jun;24:3995-8). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000565677 SCV000908260 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing

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