ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1214C>T (p.Ser405Leu)

dbSNP: rs1554298036
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000539185 SCV000625512 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 405 of the PMS2 protein (p.Ser405Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal or family history of Lynch syndrome (PMID: 31433215). ClinVar contains an entry for this variant (Variation ID: 455644). 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%. 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.
Ambry Genetics RCV002358435 SCV002656687 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-25 criteria provided, single submitter clinical testing The p.S405L variant (also known as c.1214C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1214. The serine at codon 405 is replaced by leucine, an amino acid with dissimilar 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320674 SCV004025121 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003470716 SCV004207809 uncertain significance Lynch syndrome 4 2023-06-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV002358435 SCV004359623 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-24 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 405 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 Lynch syndrome (PMID: 31433215). 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.

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