ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.833A>G (p.His278Arg)

dbSNP: rs1562664434
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780638 SCV000918069 uncertain significance not specified 2020-07-02 criteria provided, single submitter clinical testing Variant summary: PMS2 c.833A>G (p.His278Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain and DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.833A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985918 SCV001134616 uncertain significance not provided 2019-02-12 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001182717 SCV001348250 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing
Invitae RCV001229548 SCV001401995 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-03-20 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 632956). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 278 of the PMS2 protein (p.His278Arg).
Ambry Genetics RCV001182717 SCV002676611 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-22 criteria provided, single submitter clinical testing The p.H278R variant (also known as c.833A>G), located in coding exon 8 of the PMS2 gene, results from an A to G substitution at nucleotide position 833. The histidine at codon 278 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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