Submissions for variant NM_000251.3(MSH2):c.1077-10T>C

gnomAD frequency: 0.01428  dbSNP: rs17224360

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030235	SCV000107039	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	RCV000030235	SCV000052902	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Benign.
Eurofins Ntd Llc (ga)	RCV000179738	SCV000232034	benign	not specified	2014-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV000524329	SCV000262456	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000210766	SCV000267050	benign	Hereditary cancer-predisposing syndrome	2015-12-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000179738	SCV000303155	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210766	SCV000537358	benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001668139	SCV000604251	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000602995	SCV000744273	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000602995	SCV001302370	likely benign	Lynch syndrome 1	2018-01-13	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001668139	SCV001891368	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798016	SCV002042086	benign	Breast and/or ovarian cancer	2021-04-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000179738	SCV002552216	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210766	SCV002728165	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000210766	SCV002819172	benign	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000602995	SCV004015950	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000179738	SCV000257121	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030235	SCV000592488	benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 c.1077-10T>C variant was identified in at least 4 of 254 proband chromosomes (frequency: 0.016) from individuals with colon cancer and in at least 5 of 226 control chromosomes (frequency: 0.022) (Borresen 1995, Chen-Shtoyerman, Swensen 1997, Tournier 2008). The variant was also identified in the “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, and in UMD (39X as a neutral variant). The c.1077-10T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions; however, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) do not predict a greater than 10% difference in splicing, and an ex vivo splicing assay found no effect of the variant on splicing (Tournier 2008 18561205). The variant was listed in dbSNP (ID: rs17224360) “With non-pathogenic allele”, with a global minor allele frequency of 0.007 (1000 Genomes Project), and a frequency of 0.017 in 60 HapMap individuals, increasing the likelihood that this is a low frequency benign variant in certain populations of origin. In addition, several studies list or describe this variant as a polymorphism or non-pathogenic variant (Borresen 1995, Chen-Shtoyerman, Desai 2000, Jung 2006, Rubio-Del-Campo 2007, Swensen 1997, Tournier 2008). Furthermore, this variant was identified in one individual from our lab with a pathogenic variant co-occurring, increasing the likelihood of this variant having no clinical significance. 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	RCV000602995	SCV000734199	benign	Lynch syndrome 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000602995	SCV000745637	benign	Lynch syndrome 1	2015-10-07	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000179738	SCV001800051	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000179738	SCV001905862	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000179738	SCV001926141	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000179738	SCV001959846	benign	not specified		no assertion criteria provided	clinical testing