ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.40G>T (p.Ala14Ser)

dbSNP: rs876661039
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218140 SCV000279315 uncertain significance not provided 2022-03-18 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484)
Invitae RCV000536772 SCV000625653 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the PMS2 protein (p.Ala14Ser). 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: 234477). 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 RCV000562665 SCV000670762 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-31 criteria provided, single submitter clinical testing The p.A14S variant (also known as c.40G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide position 40. The alanine at codon 14 is replaced by serine, 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 RCV000562665 SCV000906971 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-18 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 14 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 reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218140 SCV001134602 uncertain significance not provided 2019-03-25 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003417796 SCV004117015 uncertain significance PMS2-related condition 2023-01-27 criteria provided, single submitter clinical testing The PMS2 c.40G>T variant is predicted to result in the amino acid substitution p.Ala14Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is reported with uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/234477/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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