Submissions for variant NM_000535.7(PMS2):c.1233A>T (p.Glu411Asp)

gnomAD frequency: 0.00006  dbSNP: rs587780040

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679349	SCV000149561	uncertain significance	not provided	2014-02-10	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1233A>T at the cDNA level, p.Glu411Asp (E411D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu411Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a conservative amino acid substitution, altering a position that is conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider PMS2 Glu411Asp to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000115652	SCV000731346	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Glu411Asp variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 1/66182 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587780040). Computational prediction tools and conservation analysis suggest that the p.Glu411Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical si gnificance of the p.Glu411Asp variant is uncertain.
Invitae	RCV000629859	SCV000750815	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 411 of the PMS2 protein (p.Glu411Asp). This variant is present in population databases (rs587780040, gnomAD 0.008%). 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: 127755). 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.
PreventionGenetics, part of Exact Sciences	RCV000679349	SCV000806168	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771586	SCV000904175	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 411 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 7/282328 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.
Ambry Genetics	RCV000771586	SCV001170670	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	clinical testing	The p.E411D variant (also known as c.1233A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1233. The glutamic acid at codon 411 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). 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.