ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.376C>G (p.His126Asp)

dbSNP: rs774135207
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000701036 SCV000829818 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-09-22 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 126 of the PMS2 protein (p.His126Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578118). 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. 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001692260 SCV001911517 uncertain significance Lynch syndrome 4 2021-09-16 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003238189 SCV002009093 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002343530 SCV002623210 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-01 criteria provided, single submitter clinical testing The p.H126D variant (also known as c.376C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 376. The histidine at codon 126 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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