ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2266G>T (p.Asp756Tyr)

gnomAD frequency: 0.00001  dbSNP: rs762206330
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481868 SCV000565422 uncertain significance not provided 2015-02-16 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2266G>T at the cDNA level, p.Asp756Tyr (D756Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp756Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Asp756Tyr occurs at a position that is conserved across species and is located in the nuclease domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Asp756Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000541533 SCV000625604 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 756 of the PMS2 protein (p.Asp756Tyr). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 418420). 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 expected to disrupt PMS2 protein function with a positive 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 RCV000571274 SCV000670741 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-26 criteria provided, single submitter clinical testing The p.D756Y variant (also known as c.2266G>T), located in coding exon 13 of the PMS2 gene, results from a G to T substitution at nucleotide position 2266. The aspartic acid at codon 756 is replaced by tyrosine, an amino acid with highly dissimilar 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.
Baylor Genetics RCV001788231 SCV002030199 uncertain significance Lynch syndrome 4 2021-02-09 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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