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

gnomAD frequency: 0.00013  dbSNP: rs374704824

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757678	SCV000149608	likely benign	not provided	2020-06-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31992580, 30653781, 31159747, 30651582, 26689913, 29785153, 28975465, 25503501, 19479271, 24027009, 25637381)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079691	SCV000166390	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington	RCV000148736	SCV000190472	uncertain significance	Polyp of colon	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, Mass General Brigham 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	RCV000757678	SCV000601854	benign	not provided	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 Diagnostics, LLC DBA Color Health	RCV000115699	SCV000910608	benign	Hereditary cancer-predisposing syndrome	2016-07-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000987846	SCV001137320	benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798337	SCV002042810	uncertain significance	Breast and/or ovarian cancer	2022-12-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212845	SCV002072250	uncertain significance	not specified	2020-04-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.620G>A, in exon 6 that results in an amino acid change, p.Gly207Glu. This sequence change has been described in the gnomAD database with a global population frequency of 0.03% and up to a 0.2% frequency in certain subpopulations (dbSNP rs374704824). The p.Gly207Glu change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly207Glu substitution. The p.Gly207Glu change has been reported in a patient with hereditary non-polyposis colorectal cancer and tumor testing showing absence of PMS2 expression and high microsatellite instability (PMID: 19479271). The p.Gly207Glu change has also been reported in a patient with breast cancer (PMID: 25503501). Functional studies using an in vitro assay demonstrated normal mismatch repair activity (PMID: 24027009). Due to these contrasting evidences, the clinical significance of the p.Gly207Glu change remains unknown at this time.
Sema4, Sema4	RCV000115699	SCV002530370	likely benign	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212845	SCV004025127	uncertain significance	not specified	2024-07-31	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.
PreventionGenetics, part of Exact Sciences	RCV003407497	SCV004114903	likely benign	PMS2-related disorder	2024-08-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).