Submissions for variant NM_000249.4(MLH1):c.588+11G>C

gnomAD frequency: 0.00993  dbSNP: rs4647258

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000490567	SCV000106777	benign	Lynch syndrome 1	2014-10-10	reviewed by expert panel	research	MAF >1%
Eurofins Ntd Llc (ga)	RCV000078419	SCV000110267	benign	not specified	2013-06-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000030228	SCV000443328	likely benign	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580337	SCV000684845	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078419	SCV000805975	benign	not specified	2016-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000059818	SCV001756426	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Invitae	RCV002054506	SCV002456836	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000580337	SCV002528755	benign	Hereditary cancer-predisposing syndrome	2020-03-28	criteria provided, single submitter	curation
Ambry Genetics	RCV000580337	SCV002652818	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.
Fulgent Genetics, Fulgent Genetics	RCV002496464	SCV002809228	benign	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-17	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315515	SCV004015875	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492305	SCV004240759	benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000078419	SCV004243137	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030228	SCV000052895	benign	Lynch syndrome	2010-09-28	no assertion criteria provided	clinical testing
Narod's Lab, University of Toronto	RCV000059818	SCV000091388	not provided	not provided		no assertion provided	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000078419	SCV000257106	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355103	SCV001549886	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 c.588+11G>C variant was not identified in the literature nor was it identified in the MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs4647258) “With other allele”, ClinVar (classified benign, reviewed by an expert panel (2014); submitters: benign by InSIGHT, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Mayo Clinic, Laboratory Corporation of America, likely benign by Illumina, and classification not provided by Narod Lab (University of Toronto)), Clinvitae (4x), Insight Colon Cancer Gene Variant Database (1x class 1), Insight Hereditary Tumors Database, and in control databases in 812 of 277078 chromosomes at a frequency of 0.002931 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 754 (7 homozygous) of 24020 chromosomes (freq: 0.03), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 47 of 34416 chromosomes (freq: 0.001), European Non-Finnish in 6 of 126604 chromosomes (freq: 0.00005), and South Asian in 1 of 30782 chromosomes (freq: 0.00003) while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	RCV000078419	SCV001808972	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000078419	SCV001905972	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078419	SCV001926099	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000078419	SCV002036855	benign	not specified		no assertion criteria provided	clinical testing