ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.178G>A (p.Asp60Asn)

gnomAD frequency: 0.00004  dbSNP: rs587782176
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167311 SCV000218158 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-14 criteria provided, single submitter clinical testing The p.D60N variant (also known as c.178G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 178. The aspartic acid at codon 60 is replaced by asparagine, an amino acid with highly 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.
Invitae RCV000226294 SCV000285087 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-05 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 60 of the PMS2 protein (p.Asp60Asn). This variant is present in population databases (rs587782176, gnomAD 0.008%). 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: 187572). 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 RCV000167311 SCV000686163 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-05 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 60 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 9/250088 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Counsyl RCV000663174 SCV000786335 uncertain significance Lynch syndrome 4 2018-04-09 criteria provided, single submitter clinical testing
GeneDx RCV001555389 SCV001776801 uncertain significance not provided 2020-08-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001555389 SCV002774689 uncertain significance not provided 2021-06-26 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000663174 SCV004019843 uncertain significance Lynch syndrome 4 2023-04-04 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320588 SCV004025139 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing

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