ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.413A>G (p.Asn138Ser) (rs769154205)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205275 SCV000262446 uncertain significance Hereditary nonpolyposis colon cancer 2019-04-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 138 of the MSH2 protein (p.Asn138Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs769154205, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 221178). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000237000 SCV000293341 uncertain significance not provided 2015-11-04 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.413A>G at the cDNA level, p.Asn138Ser (N138S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asn138Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH2 Asn138Ser occurs at a position that is not conserved and is located in the Connector domain (Lützen 2008). 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 Asn138Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564892 SCV000662251 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000564892 SCV000908276 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing

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