ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1720C>G (p.Pro574Ala)

gnomAD frequency: 0.00001  dbSNP: rs758018736
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220236 SCV000274135 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-24 criteria provided, single submitter clinical testing The p.P574A variant (also known as c.1720C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1720. The proline at codon 574 is replaced by alanine, an amino acid with highly 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 RCV000220236 SCV000686157 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-15 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 574 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 2/251364 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.
Invitae RCV000629788 SCV000750744 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-09-21 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: 230549). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs758018736, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 574 of the PMS2 protein (p.Pro574Ala).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002229221 SCV002511548 uncertain significance not specified 2022-04-05 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997849 SCV004844142 uncertain significance Lynch syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 574 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251364 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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