ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1048C>A (p.Leu350Ile)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002398511 SCV002709016 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-03 criteria provided, single submitter clinical testing The p.L350I variant (also known as c.1048C>A), located in coding exon 10 of the PMS2 gene, results from a C to A substitution at nucleotide position 1048. The leucine at codon 350 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available 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 RCV003100738 SCV003258339 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-12-21 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. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 350 of the PMS2 protein (p.Leu350Ile).
All of Us Research Program, National Institutes of Health RCV004007335 SCV004836823 uncertain significance Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 350 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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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