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: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166727 SCV000217538 likely benign Hereditary cancer-predisposing syndrome 2024-11-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000630121 SCV000751077 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-07-17 criteria provided, single submitter clinical testing 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). This variant is present in population databases (rs786203427, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 187042). 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%. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 20603082). 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 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)
All of Us Research Program, National Institutes of Health RCV003995528 SCV004844223 uncertain significance Lynch syndrome 2023-03-09 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.
Fulgent Genetics, Fulgent Genetics RCV005042340 SCV005674326 uncertain significance Lynch syndrome 4; Mismatch repair cancer syndrome 4 2024-01-22 criteria provided, single submitter clinical testing

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