Submissions for variant NM_000535.7(PMS2):c.23+10G>C

gnomAD frequency: 0.00182  dbSNP: rs192027828

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119180	SCV000153913	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212835	SCV000171045	benign	not specified	2013-12-17	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	RCV000130558	SCV000185428	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.
Counsyl	RCV000409370	SCV000489257	likely benign	Lynch syndrome 4	2016-09-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212835	SCV000596475	benign	not specified	2021-06-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130558	SCV000686179	likely benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000409370	SCV000743787	likely benign	Lynch syndrome 4	2016-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212835	SCV000806203	benign	not specified	2017-02-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705879	SCV001158630	benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409370	SCV001322571	benign	Lynch syndrome 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001705879	SCV002009096	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130558	SCV002530284	likely benign	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212835	SCV002550766	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130558	SCV002819228	benign	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149816	SCV003837744	likely benign	Breast and/or ovarian cancer	2023-06-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000409370	SCV004016605	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409370	SCV004018582	benign	Lynch syndrome 4	2023-04-21	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000409370	SCV000734571	likely benign	Lynch syndrome 4		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000409370	SCV000745851	likely benign	Lynch syndrome 4	2016-07-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212835	SCV001553285	benign	not specified		no assertion criteria provided	clinical testing	The PMS2 c.23+10G>C variant was not identified in the literature nor was it identified in the following databases: COGR, Clinvitae, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs192027828) “With other allele”, ClinVar (classified benign by Invitae, GeneDx and Ambry Genetics; and likely benign by Counsyl and Genetic Services Laboratory (University of Chicago)), and in control databases in 496 (2 homozygous) of 276428 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Consortium Feb 27, 2017). It was observed in the following populations: African in 16 of 23946 chromosomes (freq. 0.0007), other in 10 of 6460 chromosomes (freq. 0.002), Latino in 31 of 34414 chromosomes (freq. 0.0009), European Non-Finnish in 365 (2 homozygous) of 126042 chromosomes (freq. 0.003), Ashkenazi Jewish in 1 of 10138 chromosomes (freq:0.0001), European Finnish in 42 of 25794 chromosomes (freq:0.002) and South Asian in 31 of 30776 chromosomes (freq. 0.001); it was not seen in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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	RCV001705879	SCV001905843	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000212835	SCV001925477	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001705879	SCV001958167	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212835	SCV002035378	benign	not specified		no assertion criteria provided	clinical testing