ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.440C>A (p.Thr147Asn)

dbSNP: rs1554304012
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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 RCV000566927 SCV000676180 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-23 criteria provided, single submitter clinical testing The p.T147N variant (also known as c.440C>A), located in coding exon 5 of the PMS2 gene, results from a C to A substitution at nucleotide position 440. The threonine at codon 147 is replaced by asparagine, an amino acid with similar properties. This amino acid position is poorly 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 RCV000566927 SCV001347606 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces threonine with asparagine at codon 147 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.
Invitae RCV001859989 SCV002164091 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-05-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 147 of the PMS2 protein (p.Thr147Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. 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. 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. This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 486933). This variant is not present in population databases (ExAC no frequency).

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