ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.228G>T (p.Gln76His) (rs587782857)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132473 SCV000187567 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-06 criteria provided, single submitter clinical testing The p.Q76H variant (also known as c.228G>T), located in coding exon 2 of the MSH2 gene, results from a G to T substitution at nucleotide position 228. The glutamine at codon 76 is replaced by histidine, 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 6502 samples (13004 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 conserved in primates but not in lower 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 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 RCV000198343 SCV000254404 uncertain significance Lynch syndrome 2015-06-05 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 76 of the MSH2 protein (p.Gln76His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant has not been published in the literature and is present in population databases (no rsID, <0.01%). ClinVar contains an entry for this variant (RCV000132473). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. Although there is no indication that this variant causes disease, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506357 SCV000601464 uncertain significance not specified 2016-09-14 criteria provided, single submitter clinical testing

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