ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.296C>T (p.Thr99Ile)

dbSNP: rs786202835
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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 RCV000165852 SCV000216601 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The p.T99I variant (also known as c.296C>T), located in coding exon 4 of the PMS2 gene, results from a C to T substitution at nucleotide position 296. The threonine at codon 99 is replaced by isoleucine, an amino acid with similar properties. Based on protein sequence alignment, this amino acid position is highly conserved through rock hyrax, but isoleucine is the reference amino acid in the majority of lower vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000698379 SCV000827039 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 99 of the PMS2 protein (p.Thr99Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186286). 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.
Color Diagnostics, LLC DBA Color Health RCV000165852 SCV000909679 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 99 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 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320585 SCV004025131 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462190 SCV004207841 uncertain significance Lynch syndrome 4 2023-05-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003995459 SCV004842133 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 99 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 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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