ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2337G>A (p.Met779Ile) (rs41295292)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160610 SCV000211207 uncertain significance not provided 2014-09-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2337G>A at the cDNA level, p.Met779Ile (M779I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has been published in a colon cancer case-control study with an observation of 1/932 cases of colon cancer diagnosed under age 55 and was not observed in 1062 unaffected controls. Tumor testing from the one case with the MSH2 Met779Ile variant revealed microsatellite stability, yet exhibited absent MSH2 and MSH6 staining on immunohistochemistry (Barnetson 2008). MSH2 Met779Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Met779Ile occurs at a position that is conserved among mammals and is located in the ATPase domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Met779Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572885 SCV000664842 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing The p.M779I variant (also known as c.2337G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2337. The methionine at codon 779 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in one individual with colon cancer whose tumor demonstrated microsatellite stability, but showed absence of the MSH2 and MSH6 proteins on immunohistochemistry (IHC) (Barnetson RA et al. Hum. Mutat., 2008 Mar;29:367-74). This amino acid position is well conserved through mammals, but not in all 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.
Color RCV000572885 SCV000690063 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
Invitae RCV000629729 SCV000750685 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 779 of the MSH2 protein (p.Met779Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs41295292, ExAC 0.001%). This variant has been reported in an individual affected with colorectal cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90958). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their 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.

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