Submissions for variant NM_000535.7(PMS2):c.46A>G (p.Lys16Glu)

gnomAD frequency: 0.00001  dbSNP: rs777845808

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221254	SCV000276866	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.K16E variant (also known as c.46A>G), located in coding exon 2 of the PMS2 gene, results from an A to G substitution at nucleotide position 46. The lysine at codon 16 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration was also detected once 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). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599996	SCV000731506	uncertain significance	not specified	2017-03-20	criteria provided, single submitter	clinical testing	The p.Lys16Glu variant in PMS2 has not been previously reported in the literatur e individuals with Lynch syndrome, but has been reported in ClinVar (Variation I D 232676). It has also been identified in 3/17104 of East Asian chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs777845808). Computational prediction tools and conservation analysis suggest t hat the p.Lys16Glu variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. In summary, the clinical sign ificance of the p.Lys16Glu variant is uncertain.
Invitae	RCV000629695	SCV000750651	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-20	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 16 of the PMS2 protein (p.Lys16Glu). This variant is present in population databases (rs777845808, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 232676). 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 expected to disrupt PMS2 protein function with a positive 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.
GeneKor MSA	RCV000221254	SCV000822134	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221254	SCV000909685	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 16 of the PMS2 protein. Computational prediction tool 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/245504 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.
GeneDx	RCV002509320	SCV002818800	uncertain significance	not provided	2022-12-30	criteria provided, single submitter	clinical testing	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: 31159747, 11574484, 29684080, 31422818)
All of Us Research Program, National Institutes of Health	RCV003997994	SCV004842177	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 16 of the PMS2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/245504 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.