ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.764G>A (p.Ser255Asn) (rs763184168)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766744 SCV000618151 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.764G>A at the cDNA level, p.Ser255Asn (S255N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project).. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ser255Asn occurs at a position that is conserved across species and is located in the connector domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ser255Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234549 SCV000284182 uncertain significance Hereditary nonpolyposis colon cancer 2017-07-05 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 255 of the MSH2 protein (p.Ser255Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs763184168, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237406). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000519279 SCV000712633 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.Ser255Asn variant in MSH2 has not been previously reported in individuals with MSH2-associated cancer, but has been identified in 1/11556 Latino chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs763184168). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Ser255Asn variant is uncertain.

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