Submissions for variant NM_000535.7(PMS2):c.1705A>G (p.Thr569Ala)

gnomAD frequency: 0.00001  dbSNP: rs762151417

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164382	SCV000215017	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.T569A variant (also known as c.1705A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1705. The threonine at codon 569 is replaced by alanine, an amino acid with similar 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.
Invitae	RCV000231487	SCV000285083	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 569 of the PMS2 protein (p.Thr569Ala). This variant is present in population databases (rs762151417, gnomAD 0.003%). 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: 185029). 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. 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	RCV000164382	SCV000903494	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 569 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 been identified in 2/251372 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003223615	SCV002009109	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003223615	SCV003919447	uncertain significance	not provided	2023-04-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20052760)
PreventionGenetics, part of Exact Sciences	RCV003416035	SCV004115846	uncertain significance	PMS2-related disorder	2022-10-12	criteria provided, single submitter	clinical testing	The PMS2 c.1705A>G variant is predicted to result in the amino acid substitution p.Thr569Ala. This patient is heterozygous in the PMS2 gene for a sequence variant defined as c.1705A>G, which is predicted to result in the amino acid substitution p.Thr569Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6026691-T-C). This variant falls within a highly paralogous region; therefore, allele frequency data should be interpreted with caution. It is documented as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185029). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003223615	SCV004218962	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000033 (1/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003995340	SCV004844149	uncertain significance	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 569 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 been identified in 2/251372 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.
Genetic Services Laboratory, University of Chicago	RCV003150960	SCV003839890	uncertain significance	not specified	2022-09-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1705A>G, in exon 11 that results in an amino acid change, p.Thr569Ala. This sequence change does not appear to have been previously described in individuals with PMS2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.0008% (dbSNP rs762151417). The p.Thr569Ala change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. The p.Thr569Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr569Ala change remains unknown at this time.