Submissions for variant NM_000535.7(PMS2):c.1981G>A (p.Glu661Lys)

gnomAD frequency: 0.00002  dbSNP: rs778531080

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000526168	SCV000625571	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	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 661 of the PMS2 protein (p.Glu661Lys). This variant is present in population databases (rs778531080, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or uterine cancer (PMID: 27146957, 28466842, 34326862). ClinVar contains an entry for this variant (Variation ID: 455676). 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.
Ambry Genetics	RCV000570004	SCV000663490	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-19	criteria provided, single submitter	clinical testing	The p.E661K variant (also known as c.1981G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1981. The glutamic acid at codon 661 is replaced by lysine, an amino acid with similar properties. This alteration was reported as a variant of uncertain significance in a patient with a juvenile polyp diagnosed at age 36 (Jelsig AM et al. Scand. J. Gastroenterol. 2016 Sep;51(9):1118-25). This alteration was detected in a study of 1165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 Sep;105:526-533). It was also observed in 3/1182 Icelandic colorectal cancer patients with normal immunohistochemical (IHC) staining (Haraldsdottir S et al. Nat. Commun. 2017 May;8:14755). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000570004	SCV000691051	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces a highly conserved glutamic acid with lysine at codon 661 of the PMS2 protein. Computational prediction tools are inconsistent with regard to the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with colorectal cancer in the Icelandic population, whose tumors showed normal PMS2 expression (PMID: 28466842). The variant has been reported to occur at 0.29% frequency in the Icelandic population (PMID: 28466842). In the Genome Aggregation Database (gnomAD), this variant has only been identified in 4/246208 chromosomes. This variant appears to be a common benign variant in the Icelandic population, but additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612299	SCV000712912	uncertain significance	not specified	2017-02-20	criteria provided, single submitter	clinical testing	The p.Glu661Lys variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 2/66538 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs778531080). Computational prediction tools and conservation analysis suggest that the p.Glu661Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Glu661Lys variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001162167	SCV001324105	uncertain significance	Lynch syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262174	SCV001439949	uncertain significance	Breast neoplasm	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001597156	SCV001831829	uncertain significance	not provided	2022-03-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with colorectal cancer, all of whom had normal IHC staining, and in unaffected controls (Haraldsdottir 2017), and was also observed in one individual with a juvenile polyp (Jelsig 2016); This variant is associated with the following publications: (PMID: 27146957, 28466842, 11292842)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001597156	SCV002009107	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570004	SCV002530247	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000612299	SCV002550699	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001162167	SCV004205350	uncertain significance	Lynch syndrome 4	2023-10-26	criteria provided, single submitter	clinical testing