Submissions for variant NM_000249.4(MLH1):c.1558+14G>A

gnomAD frequency: 0.05554  dbSNP: rs41562513

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030214	SCV000106241	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	RCV000030214	SCV000052881	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	clinical testing	Converted during submission to Benign.
Eurofins Ntd Llc (ga)	RCV000078416	SCV000110262	benign	not specified	2013-01-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078416	SCV000303145	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000616483	SCV000443337	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-06	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000449421	SCV000537353	benign	Hereditary cancer-predisposing syndrome	2014-11-26	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000616483	SCV000781758	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001650849	SCV001156601	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Invitae	RCV001510183	SCV001717148	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001650849	SCV001868837	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28932927, 27629256, 27884173, 15996210, 24689082, 23588873, 16395668)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000078416	SCV002552493	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000449421	SCV002704389	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000616483	SCV004015866	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
Pathway Genomics	RCV000144605	SCV000189932	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078416	SCV000257053	benign	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354017	SCV000592408	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.1558+14G>A variant has been identified in 10 out of 670 proband chromosomes (frequency 0.015) in individuals with colorectal and breast cancer as well as the transitional cell carcinoma of the urinary tract; however no normal population controls were included in these studies (Furihata 2001, Kurzawski 2002, Murata 2002, Palicio 2002, Ward 2002, Lee 2005). It is listed in dbSNP database presented “With non-pathogenic allele” (ID#: rs41562513) with a “global minor allele frequency of 0.054 (1000 genomes), therefore increasing the likelihood that this variant is benign. One study demonstrated by RT-PCR that this variant did not affect splicing (Auclari_2006_16395668), increasing the likelihood this variant does not have clinical significance. This variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions, or positions +3 to +6 that are part of the splicing consensus sequence which sometimes affect splicing. In addition, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, based on the above information, this variant is classified as benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000616483	SCV000734267	benign	Colorectal cancer, hereditary nonpolyposis, type 2		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000078416	SCV001798604	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000078416	SCV001906015	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078416	SCV001919830	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078416	SCV001956792	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078416	SCV001965035	benign	not specified		no assertion criteria provided	clinical testing