Submissions for variant NM_000535.7(PMS2):c.780C>G (p.Ser260=)

gnomAD frequency: 0.82058  dbSNP: rs1805319

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030372	SCV000108381	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030372	SCV000053039	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	clinical testing	Converted during submission to Benign.
Eurofins Ntd Llc (ga)	RCV000079112	SCV000110981	benign	not specified	2014-06-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131484	SCV000186471	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
PreventionGenetics, part of Exact Sciences	RCV000079112	SCV000304738	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000601805	SCV000469738	benign	Lynch syndrome 4	2018-01-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000131484	SCV000537318	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001709475	SCV000604883	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV000755624	SCV000625690	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079112	SCV000711438	benign	not specified	2017-06-02	criteria provided, single submitter	clinical testing	p.Ser260Ser in exon 7 of PMS2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 92% (17375/18832) o f East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs1805319).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000601805	SCV000745194	benign	Lynch syndrome 4	2015-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001709475	SCV001938320	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001788999	SCV002031510	benign	Mismatch repair cancer syndrome 4	2021-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131484	SCV002530388	benign	Hereditary cancer-predisposing syndrome	2021-03-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079112	SCV002550739	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496468	SCV002813196	benign	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-08-11	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000601805	SCV004016574	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000079112	SCV000257311	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353664	SCV000592930	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.Ser260Ser variant was identified in 13 of 82 proband chromosomes (frequency: 0.159) from individuals or families with endometrial or colorectal cancer (Clendenning, 2006); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This mutation was found in conjunction with several other mutations and had normal MLPA results for PMS2 and negative immunohistochemistry (IHC) staining for PMS2. It was not predicted to be deleterious or putatively deleterious. The p.Ser260Ser variant was identified in 9 of 76 proband chromosomes (frequency: 0.12) from individuals or families with predicted HNPCC (Hendriks, 2006); However, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This mutation had 1 of 8 cases with negative PMS2 IHC staining. Nakagawa (2004) identified 2 of 14 proband chromosomes (frequency.0.15) from individuals with consecutively diagnosed endometrial or colorectal cancer in Ohio. All tumours stained positive for MSH2, MSH6 and MLH1 and negative staining for PMS2. All tumours identified were microsatellite instability (MSI) positive. A dissertation by Niessen identified 21 of 146 probands (frequency: 0.14() in individuals with colorectal cancer, early onset endometrial cancer or HNPCCC-associated tumours. 2 of 13 tested cases had negative PMS2 IHC staining and the mutation was classified as likely non-pathogenic or as a polymorphism. The patients had no germ-line mutations in MSH2, MSH6 or MLH1 and had at least 1 MSI positive tumour. Trondheim’s dissertation (2013) identified the p.Ser260Ser in 33 heterozygous and 82 homozygous cases of 238 proband chromosomes (0.828) in individuals with suspected HNPCC; however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was classified as non-pathogenic or of no clinical significance by the authors. This variant was identified in the 1000 Genomes Project in 56 of 342 chromosomes (frequency: 0.15), with prevalence in the PUR, CLM, MXL populations. Exome Variant Server project identified the variant in 1593 of 8600 European American and 699 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Ser260Ser variant has been identified in the InSiGHT Colon Cancer Database and in ClinVar. It was identified by the Emory Genetics Laboratory and is classified as no known pathogenicity and highly penetrant. It was identified by LabCorp and InSiGHT as benign in association with Lynch Syndrome. The p.Ser260Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ser260 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000601805	SCV000734565	benign	Lynch syndrome 4		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000079112	SCV001906176	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079112	SCV001926200	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079112	SCV001958403	benign	not specified		no assertion criteria provided	clinical testing