ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1518C>A (p.Asp506Glu) (rs1553366508)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572647 SCV000669791 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-09 criteria provided, single submitter clinical testing The p.D506E variant (also known as c.1518C>A), located in coding exon 10 of the MSH2 gene, results from a C to A substitution at nucleotide position 1518. The aspartic acid at codon 506 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort.This amino acid position is poorlyconserved, with glutamic acid beingthe reference amino acid in a significant proportion ofavailablevertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.It is alsopredicted to be benign by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat.2008 Jun;29(6):852-60).Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000686725 SCV000814254 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 506 of the MSH2 protein (p.Asp506Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. 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: 483701). 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 glutamic acid 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. 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.

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