Submissions for variant NM_000535.7(PMS2):c.784G>A (p.Ala262Thr)

dbSNP: rs779625900

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167024	SCV000217847	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	clinical testing	The c.784G>A (p.A262T) alteration is located in exon 7 (coding exon 7) of the PMS2 gene. This alteration results from a G to A substitution at nucleotide position 784, causing the alanine (A) at amino acid position 262 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000481531	SCV000567964	uncertain significance	not provided	2016-07-06	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.784G>A at the cDNA level, p.Ala262Thr (A262T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala262Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala262Thr occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Ala262Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000707037	SCV000836115	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 262 of the PMS2 protein (p.Ala262Thr). This variant is present in population databases (rs779625900, gnomAD 0.0009%). 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: 187306). 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	RCV000167024	SCV000904184	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 262 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 1/250764 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 of Human Genetics, University of Leipzig Medical Center	RCV001262425	SCV001440290	uncertain significance	Breast neoplasm	2019-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000167024	SCV002530389	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995548	SCV004839913	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 262 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 1/250764 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.