Submissions for variant NM_000251.3(MSH2):c.1662-9G>A

gnomAD frequency: 0.00398  dbSNP: rs17218356

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076227	SCV000107250	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV000524351	SCV000262285	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625493	SCV000430927	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.
Color Diagnostics, LLC DBA Color Health	RCV000579780	SCV000684961	benign	Hereditary cancer-predisposing syndrome	2015-02-18	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000625493	SCV000781772	uncertain significance	Lynch syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000202150	SCV000806007	benign	not specified	2017-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001711177	SCV001939607	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202150	SCV002070919	benign	not specified	2018-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579780	SCV002706545	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202150	SCV002760646	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149747	SCV003837626	benign	Breast and/or ovarian cancer	2021-11-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625493	SCV004015952	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202150	SCV000257148	uncertain significance	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354042	SCV000592514	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 c.1662-9G>A variant was identified in 3 of 584 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Montera 2000, Farrington 1998, Thompson 2013). The variant was also identified in dbSNP (ID: rs17218356) as “With other allele”, ClinVar (classified as benign by an InSiGHT expert panel (2013) and five other submitters; as likely benign by 2 submitters; and as uncertain significance by 2 submitters). The variant was not identified in UMD-LSDB. The variant was also identified in control databases in 465 (4 homozygous) of 276212 chromosomes at a frequency of 0.002, 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 386 (4 homozygous) of 23980 chromosomes (freq: 0.02), Other in 14 of 6450 chromosomes (freq: 0.002), Latino in 38 of 34372 chromosomes (freq: 0.001), European Non-Finnish in 22 of 126108 chromosomes (freq: 0.0002), East Asian in 2 of 18846 chromosomes (freq: 0.0001), and South Asian in 3 of 30556 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish or European Finnish populations. The c.1662-9G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions, although positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Furthermore, in vitro splicing analysis performed by Thompson (2013) determined the splicing of this allele to be similar to wild type. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625493	SCV000745640	benign	Lynch syndrome 1	2017-09-07	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202150	SCV001920221	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202150	SCV001959119	benign	not specified		no assertion criteria provided	clinical testing