ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1182G>T (p.Lys394Asn)

dbSNP: rs1197824645
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001010076 SCV001170222 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-05 criteria provided, single submitter clinical testing The p.K394N variant (also known as c.1182G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1182. The lysine at codon 394 is replaced by asparagine, 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 RCV001342876 SCV001536824 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-11 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 818468). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 394 of the PMS2 protein (p.Lys394Asn).
GeneDx RCV003232182 SCV003929857 uncertain significance not provided 2023-06-01 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
Color Diagnostics, LLC DBA Color Health RCV001010076 SCV004359628 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-17 criteria provided, single submitter clinical testing This missense variant replaces lysine with asparagine at codon 394 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 been identified in 1/248100 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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