ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.763A>G (p.Ser255Gly) (rs761529282)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222095 SCV000275893 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000526634 SCV000625460 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 255 of the MSH2 protein (p.Ser255Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual with endometrial cancer (PMID: 30374176). However, in that individual, pathogenic allele[s] were also identified in MSH6, which suggests that this c.763A>G variant was not the primary cause of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000222095 SCV000685128 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000757937 SCV000886466 likely benign Lynch syndrome 2018-05-09 criteria provided, single submitter research The MSH2 variant designated as NM_000251.2: c.763A>G (p.S255G) is classified as likely benign. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.08 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Computer software prediction programs also suggest the MSH2 p.S255G change is benign. Additionally, in the observed family, the variant co-occurs with a likely pathogenic variant in the MSH6 gene (p.R1076C). Immunohistochemical studies of endometrial tumor from one family member with the variant showed loss of the MSH6 protein, but no loss of IHC staining for MSH2, which is consistent with the likely pathogenic variant in the MSH6 gene. Together, this information is not consistent with a pathogenic mutation in MSH2. Bayesian analysis integrating data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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