Submissions for variant NM_000535.7(PMS2):c.1465G>A (p.Glu489Lys)

dbSNP: rs876660060

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221906	SCV000277161	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.E489K variant (also known as c.1465G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1465. The glutamic acid at codon 489 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629950	SCV000750906	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 489 of the PMS2 protein (p.Glu489Lys). This variant is not present in population databases (gnomAD no frequency). 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: 232901). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Color Diagnostics, LLC DBA Color Health	RCV000221906	SCV000906481	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 489 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 not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781759	SCV000920057	uncertain significance	not specified	2018-09-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1465G>A (p.Glu489Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277220 control chromosomes (gnomAD). 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.1465G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462505	SCV004207891	uncertain significance	Lynch syndrome 4	2023-11-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998009	SCV004844205	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV004777631	SCV005388883	uncertain significance	not provided	2024-03-05	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