Submissions for variant NM_000535.7(PMS2):c.2068A>C (p.Lys690Gln)

gnomAD frequency: 0.00007  dbSNP: rs587781909

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130250	SCV000185094	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.K690Q variant (also known as c.2068A>C), located in coding exon 12 of the PMS2 gene, results from an A to C substitution at nucleotide position 2068. The lysine at codon 690 is replaced by glutamine, an amino acid with similar properties. This alteration has been reported in a cohort of 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome (Ring KL et al. Mod. Pathol., 2016 Nov;29:1381-1389). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000222360	SCV000279603	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	Observed in individuals with endometrial, colorectal, or breast cancer (PMID: 25186627, 27443514, 33120919, 35402282, 37534630); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 25186627, 31422574, 35402282, 2744351, 33120919, 35089076, 37534630)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230692	SCV000285100	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251272	SCV001426798	uncertain significance	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2068A>C (p.Lys690Gln) results in a conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247978 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 7.1e-05), allowing no conclusion about variant significance. In addition, the variant is located in a region that is highly homologous to PMS2 pseudogenes and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.2068A>C, has been reported in the literature in individuals affected with breast cancer and in another individual with endometrial carcinoma (Tung_2015, Ring_2016, Sahin_2022, Abdel-Razeq_2022), however it was also found in two individuals in a non-cancer related cohort (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one co-occurrence with another pathogenic variants has been reported (BRCA2 c.8904delC, p.V2969fs*7, our internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222360	SCV001470047	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798443	SCV002042794	uncertain significance	Breast and/or ovarian cancer	2020-05-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001251272	SCV002065925	uncertain significance	not specified	2022-01-20	criteria provided, single submitter	clinical testing	This sequence has been previously described in individuals with breast cancer (PMID: 25186627) and endometrial cancer (PMID: 27443514). This sequence change has been described in the gnomAD database with a frequency of 0.0044% (dbSNP rs587781909); however, the frequency data for this variant in the population databases is considered unreliable due to its location in a region that is highly homologous to PMS2 pseudogenes. The p.Lys690Gln change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL) provide contradictory results for the p.Lys690Gln substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys690Gln change remains unknown at this time.
Sema4, Sema4	RCV000130250	SCV002530256	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-29	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001251272	SCV004025106	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467136	SCV004205489	uncertain significance	Lynch syndrome 4	2023-08-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130250	SCV004359563	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 690 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 11/247978 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.