ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1039-8T>A (rs193922367)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000144607 SCV000106087 benign Lynch syndrome I 2016-04-20 reviewed by expert panel research Reported 32 times by French labs. Splicing reporter minigene pCAS: normal splicing. Linkage disequilibrium with MLH1: c.1558+14G>A. Found in co-occurrence with MSH2 : c.1387_1661del (loss of exons 9 and 10).
Invitae RCV000524220 SCV000153834 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000035354 SCV000170293 benign not specified 2014-08-27 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.
Ambry Genetics RCV000131799 SCV000186850 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000035354 SCV000705547 benign not specified 2017-01-19 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000609227 SCV000781754 uncertain significance Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000609227 SCV001136398 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035354 SCV001156600 benign not specified 2018-07-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000609227 SCV001307793 benign Lynch syndrome II 2017-04-27 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Color Health, Inc RCV000131799 SCV001341845 benign Hereditary cancer-predisposing syndrome 2015-02-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030212 SCV000052879 benign Lynch syndrome 2011-12-22 no assertion criteria provided clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035354 SCV000059002 benign not specified 2008-10-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000144607 SCV000189934 benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000035354 SCV000257043 benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353426 SCV000592395 benign Endometrial carcinoma no assertion criteria provided clinical testing The MLH1 c.1039-8T>A variant was identified in 42 of 2222 proband chromosomes (frequency: 0.019) from individuals with Lynch syndrome or sporadic colorectal cancer; and was present in of 857 of 18938 control chromosomes (frequency: 0.045) from these studies (Arnold 2009, Mangold 2005, Pastrello 2011, Rouleau 2008, Thomsen 2013, Wang 1998). The 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. Two studies report the c.1039-8T>A variant at polymorphic frequencies in control individuals, increasing the likelihood that it does not have clinical importance (Arnold 2009, Thomsen 2013). In addition, statistical studies suggest that this variant had a decreased risk of HNPCC-related cancer and therefore had no effect or is likely non-pathogenic (Thomsen 2013, Pastrello 2011). In summary, based on the above information, this variant meets our lab's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000609227 SCV000734266 benign Lynch syndrome II no assertion criteria provided clinical testing
True Health Diagnostics RCV000131799 SCV000788015 likely benign Hereditary cancer-predisposing syndrome 2017-09-28 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000035354 SCV001797981 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000035354 SCV001807588 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000035354 SCV001906201 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000035354 SCV001952760 benign not specified no assertion criteria provided clinical testing

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