ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1417G>A (p.Glu473Lys)

gnomAD frequency: 0.00001  dbSNP: rs786203427
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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 RCV000166727 SCV000217538 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-13 criteria provided, single submitter clinical testing The p.E473K variant (also known as c.1417G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1417. The glutamic acid at codon 473 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in a breast cancer cohort (Tung N et al. J. Clin. Oncol. 2016 May;34(13):1460-8). 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.
Invitae RCV000630121 SCV000751077 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-07 criteria provided, single submitter clinical testing 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. 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. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 20603082). ClinVar contains an entry for this variant (Variation ID: 187042). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). This variant is present in population databases (rs786203427, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 473 of the PMS2 protein (p.Glu473Lys).
Color Diagnostics, LLC DBA Color Health RCV000166727 SCV000912094 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-02 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 473 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 been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 1/251494 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.
GeneDx RCV002466458 SCV002762248 uncertain significance not provided 2022-12-08 criteria provided, single submitter clinical testing Observed in at least one individual with breast cancer (Tung 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33281875, 20603082, 26976419)

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