ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.968C>G (p.Ser323Cys) (rs63750732)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222150 SCV000273520 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000412467 SCV000488063 uncertain significance Lynch syndrome I 2015-12-18 criteria provided, single submitter clinical testing
Invitae RCV000524426 SCV000548205 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 323 of the MSH2 protein (p.Ser323Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs63750732, ExAC 0.01%). This variant has been observed in an individual affected with clinical features of Lynch syndrome (PMID: 9240418, 10404063). ClinVar contains an entry for this variant (Variation ID: 91260). An experimental study in yeast suggests that this missense change does not alter MSH2 protein function (PMID: 17720936). 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.
GeneDx RCV000480555 SCV000565187 uncertain significance not provided 2015-02-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.968C>G at the cDNA level, p.Ser323Cys (S323C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has been identified in at least 2 individuals with colorectal cancer, one of whom had corresponding tumors with microsatellite instability (Akiyama 1997, Bai 1999). In yeast functional assays, this variant showed slightly reduced mismatch repair (MMR) activity, but demonstrated normal steady-state protein levels and intact interaction with MSH2 binding partners (Gammie 2007). MSH2 Ser323Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ser323Cys occurs at a position that is moderately conserved across mammals and is located in the lever 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 Ser323Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000222150 SCV000906530 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148634 SCV000190349 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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