ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.180C>G (p.Asp60Glu) (rs200313585)

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Total submissions: 10
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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 RCV000200992 SCV000149574 likely benign not specified 2018-01-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115665 SCV000186067 likely benign Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV001080104 SCV000218776 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200992 SCV000697313 likely benign not specified 2021-06-08 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). Seven ClinVar submissions (evaluation after 2014) cite the variant as benign (n=2) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000115665 SCV000910589 benign Hereditary cancer-predisposing syndrome 2016-05-09 criteria provided, single submitter clinical testing
Mendelics RCV000987852 SCV001137330 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587897 SCV001155039 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987852 SCV001321091 likely benign Hereditary nonpolyposis colorectal cancer type 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.
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.

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