ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.38G>A (p.Ser13Asn) (rs63749907)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235367 SCV000292975 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.38G>A at the cDNA level, p.Ser13Asn (S13N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser13Asn 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 Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ser13Asn occurs at a position that is not conserved and is located within the mismatch binding 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 Ser13Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572196 SCV000676072 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing The p.S13N variant (also known as c.38G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 38. The serine at codon 13 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000688689 SCV000816311 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 13 of the MSH2 protein (p.Ser13Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 245828). 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.
Color RCV000572196 SCV001356786 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing

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