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

gnomAD frequency: 0.07445  dbSNP: rs10254120

Total submissions: 23

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: 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.
Eurofins Ntd Llc (ga)	RCV000121854	SCV000227138	benign	not specified	2014-06-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130423	SCV000292093	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121854	SCV000304736	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000606319	SCV000469746	benign	Lynch syndrome 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	RCV000034632	SCV000604899	benign	not provided	2023-11-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	Lynch syndrome 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	Lynch syndrome 4	2017-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV001081088	SCV001000408	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	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)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000606319	SCV004016583	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076879	SCV004842174	benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
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 1	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	Lynch syndrome 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121854	SCV001953322	benign	not specified		no assertion criteria provided	clinical testing