Submissions for variant NM_000535.7(PMS2):c.2266G>A (p.Asp756Asn)

dbSNP: rs762206330

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223544	SCV000279227	uncertain significance	not provided	2015-11-05	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2266G>A at the cDNA level, p.Asp756Asn (D756N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp756Asn 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 Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asp756Asn occurs at a position that is not conserved across species, with Asparagine being the naturally occurring amino acid at this position in several species, and is located in the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Asp756Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000465930	SCV000551996	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 756 of the PMS2 protein (p.Asp756Asn). 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: 234439). 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 with a negative 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	RCV001014982	SCV001175761	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	clinical testing	The p.D756N variant (also known as c.2266G>A), located in coding exon 13 of the PMS2 gene, results from a G to A substitution at nucleotide position 2266. The aspartic acid at codon 756 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with pancreatic cancer (Hu C et al. Cancer Epidemiol Biomarkers Prev, 2016 Jan;25:207-11). This alteration was also identified in an individual with a personal and/or family history suspicious of hereditary breast and/or ovarian cancer syndrome (HBOC) (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527024	SCV001737845	uncertain significance	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2266G>A (p.Asp756Asn) results in a conservative amino acid change located in the MutL, C-terminal dimerization domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2266G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000223544	SCV002009098	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469106	SCV004207866	uncertain significance	Lynch syndrome 4	2023-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001014982	SCV004359023	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 756 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 hereditary cancer in the literature. This variant has been identified in 9/244274 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.