ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1765G>C (p.Asp589His)

gnomAD frequency: 0.00001  dbSNP: rs749727182
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483031 SCV000566221 uncertain significance not provided 2022-12-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Jarhelle et al., 2019); This variant is associated with the following publications: (PMID: 31882575)
Invitae RCV000548259 SCV000625557 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 589 of the PMS2 protein (p.Asp589His). This variant is present in population databases (rs749727182, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 31882575). ClinVar contains an entry for this variant (Variation ID: 418854). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV000561065 SCV000663463 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-15 criteria provided, single submitter clinical testing The p.D589H variant (also known as c.1765G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1765. The aspartic acid at codon 589 is replaced by histidine, an amino acid with 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000561065 SCV000911777 likely benign Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483031 SCV002046804 uncertain significance not provided 2021-03-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821390 SCV002067524 uncertain significance not specified 2020-08-12 criteria provided, single submitter clinical testing DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1765G>C, in exon 11 that results in an amino acid change, p.Asp589His. This sequence change does not appear to have been previously described in patients with PMS2-related disorders and has been described in the gnomAD database in two individuals with a low overall population frequency of 0.0008% (dbSNP rs749727182). The p.Asp589His change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. The pathogenicity of the p.Asp589His substitution appears to be contradictory using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp589His change remains unknown at this time.
Baylor Genetics RCV003470536 SCV004205413 uncertain significance Lynch syndrome 4 2023-10-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002274 SCV004844136 likely benign Lynch syndrome 2023-07-10 criteria provided, single submitter clinical testing

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