Submissions for variant NM_000535.7(PMS2):c.1488C>T (p.His496=)

gnomAD frequency: 0.02307  dbSNP: rs1805320

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076812	SCV000108298	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Ambry Genetics	RCV000128937	SCV000172811	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: 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)	RCV000174012	SCV000225234	benign	not specified	2018-03-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174012	SCV000304720	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625503	SCV000469731	likely benign	Lynch syndrome 4	2018-02-02	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.
Invitae	RCV000756560	SCV000562225	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128937	SCV000686129	benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000625503	SCV000785327	benign	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001682757	SCV000884398	benign	not provided	2023-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001682757	SCV001901682	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798272	SCV002042784	benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174012	SCV002550718	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625503	SCV004016587	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000625503	SCV004019872	benign	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Mayo Clinic Laboratories, Mayo Clinic	RCV000174012	SCV000691972	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625503	SCV000745843	benign	Lynch syndrome 4	2016-01-22	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128937	SCV000788102	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354144	SCV001548686	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.His496= variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs1805320) as “with benign allele” and ClinVar (classified as benign by Ambry Genetics, Color, Invitae, Counsyl and 6 other submitters; and as likely benign by True Health Diagnostics and Illumina). The variant was identified in control databases in 2168 of 282,774 chromosomes (70 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1934 of 24,924 chromosomes (freq: 0.08), Latino in 163 of 35,440 chromosomes (freq: 0.005), Other in 22 of 7220 chromosomes (freq: 0.003), South Asian in 10 of 30,616 chromosomes (freq: 0.0003), European in 36 of 129,170 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10,368 chromosomes (freq: 0.0001), East Asian in 1 of 19,946 chromosomes (freq: 0.00005), and Finnish in 1 of 25,090 chromosomes (freq: 0.00004). The variant was observed with a co-occurring, pathogenic PMS2 variant (p.SerGlyfs*3) in an individual with colorectal cancer (Nomura 2015), decreasing the likelihood that this variant has clinical significance. The p.His496= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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	RCV000174012	SCV001906307	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000174012	SCV001919678	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000174012	SCV001954373	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000174012	SCV002035898	benign	not specified		no assertion criteria provided	clinical testing