ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2113G>A (p.Glu705Lys) (rs267608161)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115674 SCV000149583 pathogenic not provided 2018-03-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.2113G>A at the cDNA level, p.Glu705Lys (E705K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been reported in individuals with Lynch Syndrome and in individuals with Lynch syndrome-related tumors that demonstrate microsatellite instability (MSI) and/or absence of PMS2 on immunohistochemistry (IHC) (Clendenning 2006, Halvarsson 2006, Lagerstedt Robinson 2007, Senter 2008, Vaughn 2013, ten Broeke 2015, Shirts 2016). PMS2 Glu705Lys has also been reported with a second PMS2 variant in a child with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome with absent MLH1/PMS2 on IHC (Lavoine 2015). Functional studies have demonstrated that PMS2 Glu705Lys is defective in endonuclease and mismatch repair activities leading to increased genomic mutation rates and cancer predisposition (Kadyrov 2006, Erdeniz 2007, Deschenes 2007, Martinez 2010, van Oers 2010, Drost 2013). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology. This variant is located in the Endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
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 2019-09-19 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
Invitae RCV000524457 SCV000551983 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 705 of the PMS2 protein (p.Glu705Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in the population databases (rs267608161, ExAC), however the frequency data is considered unreliable due to poor data quality at this position in the ExAC database and the presence of a pseudogene that has strong homology to this region. This variant has been observed in several individuals and families affected with breast cancer, colorectal cancer and/or suspected Lynch syndrome (PMID: 26110232, 18602922, 23012243, 16619239, 26681312, 26845104, 27601186, 27978560, 28466842). It has also been observed in individuals with clinical features of constitutional mismatch repair deficiency syndrome (PMID: 26318770, Invitae). In at least one individual, the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91328). Experimental studies have shown that this missense change disrupts PMS2 mismatch repair activity in vitro, but does not interfere with wild-type PMS2 function in a dominant-negative manner (PMID: 24027009, 20176959, 17029773, 17567544, 16873062, 20624957). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000115674 SCV000892767 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144654 SCV000189981 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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