Submissions for variant NM_000251.3(MSH2):c.1387-8G>T

gnomAD frequency: 0.00143  dbSNP: rs187525243

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000625492	SCV000107164	benign	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.001 (0.00017)
GeneDx	RCV000202101	SCV000170337	benign	not specified	2013-12-12	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.
Invitae	RCV001083687	SCV000252652	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000126811	SCV000267051	benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000202101	SCV000303156	likely benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126811	SCV000537404	benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202101	SCV000595828	likely benign	not specified	2017-03-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625492	SCV000745639	likely benign	Lynch syndrome 1	2015-08-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000625492	SCV001135729	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679289	SCV001152277	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202101	SCV001156595	benign	not specified	2018-10-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625492	SCV001304348	likely benign	Lynch syndrome 1	2019-05-07	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798017	SCV002042088	benign	Breast and/or ovarian cancer	2020-07-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126811	SCV002528845	benign	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202101	SCV002552229	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000126811	SCV002695929	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126811	SCV002819177	benign	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625492	SCV004015944	likely benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030239	SCV000052906	benign	Lynch syndrome	2015-02-16	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202101	SCV000257139	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030239	SCV000592501	benign	Lynch syndrome		no assertion criteria provided	clinical testing	The c.1387-8G>T variant has been reported in the literature in at least 4 of 224 probands who either had CRC or met criteria for Lynch syndrome (Tournier_2008_18561205, Lamberti_2006_17095871, Levene_2003_14574163, Van_Pruijenbroek_2008 18415027). However, population controls were not included in these studies such that the full spectrum of benign variation may not yet have been defined for this gene, increasing the possibility that this may be a benign variant. This variant was identified in the EVS server, dbSNP and the 1000 genomes project as a low frequency variant in both Caucasian and black populations increasing the likelihood this variant is benign. In addition, this variant did not have any effect in an ex-vivo splicing assay (Tournier_2008_18561205) increasing the likelihood that this variant does not have clinical significance. Furthermore, this variant was reported in two studies in two individuals, both had high microsatellite instability (MSI), however, immunohistochemistry for MLH1, MSH2, MSH6 was intact, increasing the likelihood this variant does not result in loss of function of the protein product (Lamberti_2006_17095871, Van_Pruijenbroek_2008 18415027). The c.1387-8G>T 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. In summary, based on the above information, this variant is classified as benign.
True Health Diagnostics	RCV000126811	SCV000805265	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679289	SCV001919914	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000202101	SCV001928887	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679289	SCV001956919	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679289	SCV001964370	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000202101	SCV001977644	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000202101	SCV002035915	benign	not specified		no assertion criteria provided	clinical testing