ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.677+3A>G (rs267607780)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075806 SCV000106820 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration: full inactivation of variant allele
Ambry Genetics RCV000222833 SCV000276798 pathogenic Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation
GeneDx RCV000201996 SCV000568565 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.677+3A>G or IVS8+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 8 of the MLH1 gene. This variant affects the nearby natural splice donor site and has been shown to result in abnormal gene splicing via exon 8 skipping (Krüger 2003, Naruse 2009, Betz 2010). MLH1 c.677+3A>G was observed in several individuals with colorectal cancer and at least one with pancreatic cancer (Montera 2000, Krüger 2003, Casey 2005, Mangold 2005, Grant 2014, Rotsy 2016). This variant was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). The adenine (A) nucleotide that is altered is conserved across species. Based on the current evidence, we consider MLH1 c.677+3A>G to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075806 SCV000592368 pathogenic Lynch syndrome 2016-10-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000201996 SCV000702138 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Color RCV000222833 SCV000905466 pathogenic Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing
Invitae RCV000812851 SCV000953179 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-01-09 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 15713769, 15289847, 12655562, 19669161, 26895986, 15365996). This variant is also known as IVS8+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90315). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 12655562, 19669161, 19685281). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201996 SCV000257112 pathogenic not provided no assertion criteria provided research

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