Submissions for variant NM_000179.3(MSH6):c.1164C>T (p.His388=)

gnomAD frequency: 0.01384  dbSNP: rs55708305

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074639	SCV000107839	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1% & Multifactorial likelihood analysis posterior probability <0.001
Invitae	RCV000524102	SCV000153934	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130493	SCV000185362	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)	RCV000035317	SCV000203035	benign	not specified	2014-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035317	SCV000302866	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094632	SCV000430958	likely benign	Lynch syndrome 5	2018-01-12	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	RCV000130493	SCV000685173	benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000035317	SCV001158618	benign	not specified	2019-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001711146	SCV001940728	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130493	SCV002535604	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035317	SCV002552289	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001094632	SCV004015994	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035317	SCV000058965	likely benign	not specified	2008-07-10	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035317	SCV000257206	benign	not specified		no assertion criteria provided	research
True Health Diagnostics	RCV000130493	SCV000788041	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356459	SCV001551636	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.His388= variant was identified in 4 of 908 proband chromosomes (frequency: 0.004) from cases with high risk breast and colon cancer and was not identified in 332 chromosomes from healthy individuals (Kolodner 1999, Perez-Cabornero 2009, Sanchez 2005, Wasielewski 2009). The variant was identified in the following databases: dbSNP (ID: rs55708305) “With other allele”, ClinVar (classified benign, reviewed by an expert panel 2013, submitters: benign by InSIGHT, Invitae, Ambry Genetics, EGL Genetic Diagnostics, Prevention Genetics and Mayo Clinic, and likely benign by Illumina and the Laboratory for Molecular Medicine), Clinvitae (4x), UMD-LSDB (8x neutral), Insight Colon Cancer Gene Variant Database (4x), Mismatch Repair Genes Variant Database (3x), Insight Hereditary Tumors Database (4x) and was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 1240 (29 homozygous) of 276736 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1060 of 24012 chromosomes (freq: 0.04), Other in 18 of 6454 chromosomes (freq: 0.003), Latino in 125 of 34402 chromosomes (freq: 0.004), European Non-Finnish in 37 of 126300 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.His388= 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. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000035317	SCV001809328	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035317	SCV001917768	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035317	SCV002036563	benign	not specified		no assertion criteria provided	clinical testing