ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.11C>T (p.Ala4Val)

dbSNP: rs745361721
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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 RCV000570482 SCV000676172 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-08 criteria provided, single submitter clinical testing The p.A4V variant (also known as c.11C>T), located in coding exon 1 of the PMS2 gene, results from a C to T substitution at nucleotide position 11. The alanine at codon 4 is replaced by valine, an amino acid with similar properties. This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health RCV000570482 SCV000909092 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-09 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 4 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 been identified in 1/250258 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 RCV001301831 SCV001491014 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-02-28 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: 486928). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the PMS2 protein (p.Ala4Val).

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