Submissions for variant NM_000535.7(PMS2):c.1234A>G (p.Lys412Glu)

dbSNP: rs587778616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218590	SCV000274275	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	clinical testing	The p.K412E variant (also known as c.1234A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1234. The lysine at codon 412 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). 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.
GeneDx	RCV000766288	SCV000279847	uncertain significance	not provided	2016-02-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1234A>G at the cDNA level, p.Lys412Glu (K412E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. In addition, PMS2 Lys412Glu 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 Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Lys412Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional 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 Lys412Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance..
Invitae	RCV000630224	SCV000751180	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 412 of the PMS2 protein (p.Lys412Glu). 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: 135064). 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.
Color Diagnostics, LLC DBA Color Health	RCV000218590	SCV001353136	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498578	SCV002814789	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-04-22	criteria provided, single submitter	clinical testing
ITMI	RCV000121838	SCV000086036	not provided	not specified	2013-09-19	no assertion provided	reference population