Submissions for variant NM_000535.7(PMS2):c.418A>G (p.Asn140Asp)

gnomAD frequency: 0.00001  dbSNP: rs35911407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220217	SCV000279229	uncertain significance	not provided	2015-12-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.418A>G at the cDNA level, p.Asn140Asp (N140D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has been reported in at least one Chinese individual with colon cancer (Sheng 2010). PMS2 Asn140Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asn140Asp occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Asn140Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001227570	SCV001399932	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-06-04	criteria provided, single submitter	clinical testing	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: 234440). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 20698049). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 140 of the PMS2 protein (p.Asn140Asp). 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	RCV002327096	SCV002627008	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The p.N140D variant (also known as c.418A>G), located in coding exon 5 of the PMS2 gene, results from an A to G substitution at nucleotide position 418. The asparagine at codon 140 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was detected in a cohort of 26 unrelated Chinese hereditary nonpolyposis colorectal cancer (HNPCC) probands (Sheng X et al. World J Gastroenterol, 2010 Aug;16:3847-52). This amino acid position is not 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.
All of Us Research Program, National Institutes of Health	RCV003998615	SCV004825552	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 140 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 been reported in a cohort of Chinese individuals affected with Lynch syndrome (PMID: 20698049). This variant has been identified in 1/31406 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.