ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys)

gnomAD frequency: 0.00003  dbSNP: rs267608161
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115674 SCV000149583 pathogenic not provided 2023-07-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: defective homologous recombination and mismatch repair activities (Kadyrov et al., 2006; Erdeniz et al., 2007; Deschenes et al., 2007; Martinez et al., 2010; van Oers et al., 2010; Drost et al., 2013); Reportedly observed in the compound heterozygous state in a patient with constitutional mismatch repair deficiency in published literature (Lavoine et al., 2015); 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: 26232782, 26945061, 16873062, 26110232, 27978560, 26318770, 32652087, 20624957, 22290698, 17029773, 18602922, 16619239, 17312306, 17567544, 18768816, 25512458, 22290424, 23612316, 16817031, 26704428, 9419979, 20176959, 24027009, 25430799, 26845104, 23012243, 26719141, 26681312, 27601186, 30809968, 31433215, 32642664, 30572730, 31992580, 31447099, 33453991, 33510387, 28888541, 30787465, 35189042, 35451682, 18619468)
University of Washington Department of Laboratory Medicine, University of Washington RCV000076843 SCV000266218 pathogenic Lynch syndrome 2016-03-25 criteria provided, single submitter clinical testing This variant has been observed several times as one of two PMS2 variants in a patient with MSI high colon cancer (Clendenning 2006). In addition, this variant has been shown to affect mismatch repair in yeast models (Erdeniz 2007, Deschenes 2007). Several reports have documented consistent loss of PMS2 expression in the tumors of individuals with this variant (Clendenning 2006, Senter 2008, Moline 2013). Family studies provided evidence for segregation of this variant with MSI high cancer showing loss of PMS2 (internal laboratory data). There are too few reports of this variant to determine an independent estimate relative colon cancer risk for this variant.
Ambry Genetics RCV000223542 SCV000274276 likely pathogenic Hereditary cancer-predisposing syndrome 2023-12-09 criteria provided, single submitter clinical testing The p.E705K variant (also known as c.2113G>A), located in coding exon 12 of the PMS2 gene, results from a G to A substitution at nucleotide position 2113. The glutamic acid at codon 705 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple patients with Lynch syndrome-associated malignancies, including tumors showing loss of PMS2 via immunohistochemistry and/or microsatellite instability (Miyaki M et al. Oncogene. 1997;15(23):2877-81; Senter L et al. Gastroenterology. 2008.135(2); 419-428; Miyaki M et al. Oncogene. 1997 Dec;15(23):2877-81; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835; Haraldsdottir S et al. Nat Commun. 2017 May;8:14755, Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Thutkawkorapin J et al. Mol Genet Genomic Med, 2019 05;7:e605; Ambry internal data). This alteration has been detected in at least two individuals with features consistent with constitutional mismatch repair deficiency and had an additional PMS2 mutation (Lavoine et al. J. Med. Genet. 2015 Nov;52(11):770-8; Ambry internal data). In a functional study, the p.E705K variant inhibited mismatch repair activity in mammalian or yeast cells when it was expressed in excess amounts relative to the wild-type PMS2. However, it did not affect protein stability or its interaction with MLH1, suggesting that the p.E705K variant may behave in a recessive manner (Deschenes SM et al. Cancer Lett. 2007;249(2):148-56). In another functional study, analysis of this alteration in mice showed an increase in genomic mutation frequency and tumor incidence (van Oers JM et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul; 107(30):13384-9). In addition, this variant has been identified to have deficient function in several other assays (Ortega J et al. Cell Res, 2021 May;31:542-553; D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000524457 SCV000551983 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-12-26 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 705 of the PMS2 protein (p.Glu705Lys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16619239, 18602922, 23012243, 26110232, 26318770, 26681312, 26845104, 27601186, 27978560, 28466842; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91328). 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%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 16873062, 17029773, 17567544, 20176959, 20624957, 24027009). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000115674 SCV000892767 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000115674 SCV001450312 pathogenic not provided 2016-02-18 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000115674 SCV002009105 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000223542 SCV002530261 pathogenic Hereditary cancer-predisposing syndrome 2022-01-25 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298464 SCV002598654 pathogenic Hereditary nonpolyposis colon cancer 2022-09-22 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2113G>A (p.Glu705Lys) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 226056 control chromosomes. c.2113G>A has been reported in the literature in multiple individuals affected with Turcot syndrome or Lynch Syndrome (e.g. Miyaki_1997, Haraldsdottir_2017, Okkels_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Martinez_2010, Drost_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149756 SCV003838386 likely pathogenic Breast and/or ovarian cancer 2022-03-09 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000115674 SCV004025105 likely pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003452990 SCV004187581 likely pathogenic Lynch syndrome 4 2023-09-21 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16873062, 20624957].
Baylor Genetics RCV003452990 SCV004205388 pathogenic Lynch syndrome 4 2023-10-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115674 SCV004218975 pathogenic not provided 2022-11-29 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000078 (9/114962 chromosomes,, is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals and families (PMID: 18602922 (2008), 27978560 (2016), 36134613 (2022)) affected with colorectal cancer (PMIDs: 16619239 (2006), 28466842 (2017), 30809968 (2019), 31433215 (2019), 31992580 (2020), 32652087 (2020), 33359728 (2022)) or a Lynch-syndrome-associated cancer (PMID: 23012243 (2013), 26681312 (2015), 23612316 (2013), 28888541 (2017)). The variant was also reported in a patient affected with CMMRD who had another variant in the PMS2 gene, although tumor testing showed a lack of both MLH1 and PMS2 proteins (PMID: 26318770 (2015)). Functional studies have shown that this variant causes defective DNA mismatch repair (PMIDs: 16873062 (2006), 17029773 (2007), 17567544 (2007), 20176959 (2010), 24027009 (2013), 33453991 (2020), 33510387 (2021), 35189042 (2022)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000223542 SCV004359549 pathogenic Hereditary cancer-predisposing syndrome 2022-10-10 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 705 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). The variant has been used as a non-functional control in a cell-free mismatch repair activity assay (PMID 24027009). It has also been shown to result in loss of PMS2 function in an endonuclease assay, a 6-thioguanine sensitivity assay and a mutator phenotype assay (PMID: 16873062, 17029773, 17567544). This variant has been detected in an individual affected with Turcot syndrome (PMID: 9419979), and in over ten individuals and families affected with Lynch syndrome-associated cancer (PMID: 16619239, 17312306, 18602922, 23612316, 26110232, 26681312, 26845104, 27601186, 27978560, 28466842, 30572730, 30809968). This variant also has been detected in an individual with a pathogenic covariant in PMS2 affected with biallelic constitutional mismatch repair deficiency syndrome (PMID: 26318770). This variant has been identified in 10/257172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000076843 SCV004847564 likely pathogenic Lynch syndrome 2020-05-13 criteria provided, single submitter clinical testing The p.Glu705Lys variant in PMS2 has been reported in 4 individuals with Lynch-related cancers (Miyaki 1997, Goldberg 2015, Susswein 2015, Pearlman 2017) and in a compound heterozygous individual with constitutional mismatch repair syndrome, in trans with c.[706?_903+?del] (Lavoine 2015). It has also been identified in 0.01% (9/114953) of European chromosomes by gnomAD ( This variant has also been reported in ClinVar (Variation ID 91328). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Martinez 2010, Drost 2013); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch Syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PS4_Supporting, PM3.
Pathway Genomics RCV000144654 SCV000189981 uncertain significance Lynch syndrome 1 2014-07-24 no assertion criteria provided clinical testing

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