ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.620G>A (p.Gly207Glu) (rs374704824)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212845 SCV000149608 uncertain significance not specified 2017-09-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.620G>A at the cDNA level, p.Gly207Glu (G207E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant, previously reported as c.676G>A based on a different reference sequence, has been reported in one individual from a Hereditary Nonpolyposis Colorectal Cancer (HNPCC) family and in one individual with breast cancer (Montazer Haghighi 2009, Maxwell 2014). The individual from the HNPCC family had colon cancer demonstrating microsatellite instability and absence of PMS2 protein expression, suggesting potential mismatch repair deficiency (Montazer Haghighi 2009). However, Drost et al. (2013) performed an in vitro assay which found that the relative repair efficiency of PMS2 Gly207Glu was significantly higher than the repair deficient control, indicating normal mismatch repair activity. PMS2 Gly207Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Gly207Glu occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located within the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available and somewhat conflicting information, it is unclear whether PMS2 Gly207Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001079691 SCV000166390 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115699 SCV000187415 likely benign Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
CSER _CC_NCGL, University of Washington RCV000148736 SCV000190472 uncertain significance Colon polyps 2015-07-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 24 year old female with a personal history of 11-20 colon polyps and family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212845 SCV000540067 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD and has been seen in one person with colorectal cancer. It is present in gnomAD at a Max MAF of 0.19% (61/30900 South Asian chrs - too high for disease incidence). It is classified in ClinVar with 1 star as VUS by GeneDx, Ambry, and CSER_CC_NCGL, and as Likely Benign by Invitae.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212845 SCV000601854 benign not specified 2019-12-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212845 SCV000697375 benign not specified 2021-03-07 criteria provided, single submitter clinical testing Variant summary: PMS2 c.620G>A (p.Gly207Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutL domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The nucleotide sequence surrounding this genomic location is unique to PMS2 and not found in the psuedogene, thus identification of this variant in patients and controls is expected to truly be in the PMS2 gene. The variant allele was found at a frequency of 0.00037 in 251990 control chromosomes, predominantly at a frequency of 0.002 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.620G>A has been reported in the literature in individuals affected with Lynch Syndrome, Breast/Ovarian Cancers (example, Montazer Haghighi_2009, Maxwell_2014, Warren_2015, Goldescu_2018, Lu_2015, Siraj_2017, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (Tung_2015, ATM c.1564_1565del , p.Glu522Ilefs*43; our laboratory, BRCA1 c.5266dupC, p.Q1756fs*74; CHEK2 c.1100delC, p.Thr367fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in mildly defective in MMR activity (~70% of wild type activity; Drost_2013), with activity significantly higher than the repair deficient control. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign, n=4, likely benign, n=1, VUS, n=6). Many submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging consensus towards a neutral outcome as evidence outlined above, the variant was classified as benign.
GeneKor MSA RCV000115699 SCV000822136 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757678 SCV000885992 uncertain significance not provided 2017-12-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115699 SCV000910608 benign Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing
Mendelics RCV000987846 SCV001137320 benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000123090 SCV000592927 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The PMS2 p.Gly207Glu variant was identified in 1 of 1184 proband chromosome (frequency: 0.0008) from individuals or families with Hereditary Non-Polyposis Colorectal Cancer and was not identified in 496 control chromosomes from healthy individuals (Montazer Haghighi 2009). In the same publication the patient who carried the p.Gly207Glu variant had a tumor that was negative for PMS2 IHC but was MSI-high suggesting that the variant may have clinical significance (Montazer Haghighi 2009). The variant was also identified in dbSNP (ID: rs374704824 as "With Uncertain significance, other allele"), ClinVar (6x as uncertain significance and 2x as likely benign), Cosmic (as a somatic mutation in squamous cell carcinoma), and Insight Hereditary Tumors Database (as Unknown). The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 96 of 277222 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), European Non-Finnish in 33 of 126724 chromosomes (freq: 0.0003), and South Asian in 62 of 30782 chromosomes (freq: 0.002) and was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. An in vitro assay showed that a recombinant protein with the p.Gly207Glu variant was positive for MMR activity also suggesting that the variant does not have clinical significance (Drost 2013). The p.Gly207 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, given the conflicting evidence, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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