Submissions for variant NM_000535.7(PMS2):c.1828A>G (p.Lys610Glu)

gnomAD frequency: 0.00004  dbSNP: rs199700509

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168273	SCV000218945	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	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 610 of the PMS2 protein (p.Lys610Glu). This variant is present in population databases (rs199700509, gnomAD 0.005%). This missense change has been observed in individual(s) with lung cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 188287). 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.
GeneDx	RCV000486825	SCV000567198	uncertain significance	not provided	2022-11-10	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; Observed in an individual with lung cancer (Lu et al., 2015); This variant is associated with the following publications: (PMID: 26689913)
Ambry Genetics	RCV000574365	SCV000663448	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.K610E variant (also known as c.1828A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1828. The lysine at codon 610 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in a lung cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun, 2015 Dec;6:10086). 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.
Color Diagnostics, LLC DBA Color Health	RCV000574365	SCV000902934	likely benign	Hereditary cancer-predisposing syndrome	2015-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000486825	SCV001155028	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PMS2: PM2, BP4
Sema4, Sema4	RCV000574365	SCV002530232	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003468829	SCV004205398	uncertain significance	Lynch syndrome 4	2023-10-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995619	SCV004844127	likely benign	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing