ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.299A>C (p.Gln100Pro)

gnomAD frequency: 0.00001  dbSNP: rs747771951
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165733 SCV000216474 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-24 criteria provided, single submitter clinical testing The p.Q100P variant (also known as c.299A>C), located in coding exon 4 of the PMS2 gene, results from an A to C substitution at nucleotide position 299. The glutamine at codon 100 is replaced by proline, 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.
Invitae RCV000470281 SCV000552054 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 100 of the PMS2 protein (p.Gln100Pro). This variant is present in population databases (rs747771951, gnomAD 0.03%). 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: 186187). 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 with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 RCV000165733 SCV000686187 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-25 criteria provided, single submitter clinical testing This missense variant replaces glutamine with proline at codon 100 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 34172528), or breast cancer (PMID: 32068069). This variant has been identified in 4/238842 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.

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