Submissions for variant NM_000535.7(PMS2):c.180C>G (p.Asp60Glu)

gnomAD frequency: 0.00088  dbSNP: rs200313585

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076828	SCV000108315	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV000587897	SCV000149574	likely benign	not provided	2020-09-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26247049, 24027009, 26336887, 27435373)
Ambry Genetics	RCV000115665	SCV000186067	likely benign	Hereditary cancer-predisposing syndrome	2018-09-06	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.
Invitae	RCV001080104	SCV000218776	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200992	SCV000697313	benign	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.180C>G (p.Asp60Glu) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 281538 control chromosomes, predominantly at a frequency of 0.00075 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 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 Non-Finnish European origin. However, this data must be interpreted with caution as there is high homology to a pseudogene, which may artificially inflate the allele frequency. c.180C>G has been reported in the literature in individuals affected with Lynch Syndrome or prostate cancer (Grant_2015, van der Klift_2016, Mateo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Functional studies showed that this variant was not associated with aberrant splicing (van der Klift_2015) and MMR efficiency at 70% of the wild-type levels (Drost_2013). Multiple ClinVar submissions (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000115665	SCV000910589	benign	Hereditary cancer-predisposing syndrome	2016-05-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000987852	SCV001137330	likely benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587897	SCV001155039	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PMS2: BP1, BS3:Supporting
Illumina Laboratory Services, Illumina	RCV000987852	SCV001321091	likely benign	Lynch syndrome 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798273	SCV002042791	likely benign	Breast and/or ovarian cancer	2019-05-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200992	SCV002069910	benign	not specified	2021-08-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115665	SCV002530230	benign	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200992	SCV004025138	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000200992	SCV001553127	benign	not specified		no assertion criteria provided	clinical testing	The PMS2 p.Asp60Glu variant was identified in 2 of 792 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (van der Klift 2016). The variant was also identified in the following databases: dbSNP (ID: rs200313585) as "With Likely benign allele", ClinVar (4x likely benign, including review by expert panel InSiGHT, 1x benign), Clinvitae, and Insight Hereditary Tumors Database (6x, likely not pathogenic/little clinical significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 271 of 276504 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 24012 chromosomes (freq: 0.0002), Other in 13 of 6456 chromosomes (freq: 0.002), Latino in 2 of 34384 chromosomes (freq: 0.00006), European in 95 of 126292 chromosomes (freq: 0.0008), and Finnish in 157 of 25784 chromosomes (freq: 0.006). The variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. A functional study utilizing a cell-free assay found c.180C>G in vitro mismatch repair activity conserved (Drost 2013). Another study investing the splicing pattern of c.180C>G through use of a minigene assay found no aberrant splicing (van der Klift 2015). The p.Asp60 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587897	SCV001906193	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000587897	SCV001924663	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000200992	SCV001979773	benign	not specified		no assertion criteria provided	clinical testing