ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1642G>A (p.Asp548Asn)

gnomAD frequency: 0.00001  dbSNP: rs374591423
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195742 SCV000254603 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 548 of the PMS2 protein (p.Asp548Asn). This variant is present in population databases (rs374591423, gnomAD 0.003%). 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: 216453). 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.
Color Diagnostics, LLC DBA Color Health RCV000775362 SCV000909650 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-31 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 548 of the PMS2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251052 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV001546990 SCV001766606 uncertain significance not provided 2023-04-14 criteria provided, single submitter clinical testing Observed in an individual with breast cancer who also harbored a pathogenic BRCA1 variant (Nikitin et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32547938)
Sema4, Sema4 RCV000775362 SCV002530211 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-27 criteria provided, single submitter curation
Ambry Genetics RCV000775362 SCV002704590 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-30 criteria provided, single submitter clinical testing The p.D548N variant (also known as c.1642G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1642. The aspartic acid at codon 548 is replaced by asparagine, an amino acid with highly similar properties. In a study of 711 hereditary breast cancer patients and 492 healthy controls, this alteration was identified in one breast cancer patient who also carries a BRCA1 truncating alteration (Nikitin AG et al. Front Oncol, 2020 May;10:666). 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.

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