ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.59G>A (p.Arg20Gln) (rs10254120)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076879 SCV000108372 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Ambry Genetics RCV000130423 SCV000185287 benign Hereditary cancer-predisposing syndrome 2014-11-03 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121854 SCV000227138 benign not specified 2014-06-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130423 SCV000292093 benign Hereditary cancer-predisposing syndrome 2014-11-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121854 SCV000304736 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000606319 SCV000469746 benign Hereditary nonpolyposis colorectal cancer type 4 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282883 SCV000604899 benign none provided 2020-08-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121854 SCV000711437 benign not specified 2016-09-01 criteria provided, single submitter clinical testing p.Arg20Gln in exon 2 of PMS2: This variant is not expected to have clinical sign ificance because it has been identified in 7.8% (9003/115162) of total chromosom es by the Exome Aggregation Consortium (ExAC), including 410 homozygous individu als (http://exac.broadinstitute.org; dbSNP rs10254120). Furthermore, it was clas sified as benign on Sep. 5, 2013 by the ClinGen-approved InSiGHT expert panel (C linVar SCV000108372.2).
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000606319 SCV000743785 likely benign Hereditary nonpolyposis colorectal cancer type 4 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000606319 SCV000745199 benign Hereditary nonpolyposis colorectal cancer type 4 2017-05-31 criteria provided, single submitter clinical testing
Invitae RCV001081088 SCV001000408 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000034632 SCV001893530 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28932927, 24728327, 26811195, 27153395, 7704024, 27884173, 8072530, 18768816, 24689082, 24618965, 22949387, 21239990, 23981578, 22703879)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034632 SCV000043439 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121854 SCV000086056 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144652 SCV000189979 benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353558 SCV000592920 benign Endometrial carcinoma no assertion criteria provided clinical testing PMS2, EXON 2, c.59G>A, p.Arg20Gln, Benign (ACMG 5) In the (8072530_Nicolaides_1994, 16472587_Hendriks_2006 , 18768816_Marionvic-Terzic_2008 21239990_Pastrello_2011 , 22703879_Johnston_2012 , 23709753_Borras_2013 23981578_Wang_2013, 24618965_Dewey_2014, 24689082_Hansen_2014, 24728327_Bodian_2014, 22949387_Thompson_2013) articles, a total of 8 proband alleles of 112 (frequency: 0.027) tested positive for the variant and of the controls a total of 31 alleles of 379 tested positive (frequency: 0.082). In 22703879_johnston_2012, the variant was found in 77 of 572 individuals not included in the previous numbers; many of the articles suggest that the variant is a polymorphism and is benign. The variant was also identified in dbSNP (ID: rs10254120 ) “With untested allele”, with a minor allele frequency of 7.024% (1000 Genomes Project), HGMD, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, ClinVar database. In the ClinVar database, 5 separate submitters classify the variant as benign. This variant was identified in the 1000 Genomes Project in 153 of 2178 chromosomes (frequency: 0.07), Exome Variant Server project in 272 of 4320 European American (frequency: 0.06) and in 246 of 2714 African American alleles (frequency: 0.09), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Arg20 residue is not conserved in mammals and the variant amino acid Glycine (Gly) is present in Trichoplax adhaerens, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The c.59G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000121854 SCV000691981 benign not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000606319 SCV000734569 benign Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000121854 SCV001906414 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000121854 SCV001919563 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000121854 SCV001953322 benign not specified no assertion criteria provided clinical testing

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