ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1668-1G>A (rs267607845)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214110 SCV000278026 pathogenic Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000214110 SCV000684764 pathogenic Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075300 SCV000592416 pathogenic Lynch syndrome 2015-03-03 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075300 SCV000106296 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical acceptor splice site (splicing aberration not quantified)
Invitae RCV000629693 SCV000750649 pathogenic Hereditary nonpolyposis colon cancer 2018-10-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with Lynch syndrome (PMID: 14635101, 15855432, 17095871, 19267393, 21868491). Experimental studies have shown that this sequence change disrupts splicing and leads to an out-of-frame skipping of exon 15 of MLH1 mRNA (PMID: 19267393). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000075300 SCV000731290 pathogenic Lynch syndrome 2016-12-01 criteria provided, single submitter clinical testing The c.1668-1G>A variant in MLH1 has been reported in at least 4 individuals with Lynch Syndrome (Lamberti 2006, Arnold 2009, Perez-Carbonell 2012, Shirts 2016) and was found to segregate with disease in 2 additional affected individuals in one family (Arnold 2009). This variant was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus s equence and has been observed to cause altered splicing leading to an abnormal o r absent protein (Arnold 2009, Perez-Carbonell 2012). Heterozygous loss of funct ion of the MLH1 gene is an established disease mechanism in Lynch Syndrome. Addi tionally, this variant has been classified as Likely pathogenic on Sep 5, 2013 b y the ClinGen-approved InSiGHT panel (ClinVar SCV000106296.2). In summary, this variant meets our criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.
University of Washington Department of Laboratory Medicine,University of Washington RCV000075300 SCV000266075 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1668-1G>A was observed in one family with several cases of early-onset colon and endometrial cancer (Shirts et al 2016, PMID 26845104). It was also seen as an apparent passenger mutation in a tumor with other somatic mutations apparently responsible for the observed MSI status, reducing the likelihood of pathogenicity (Shirts et al 2018, PMID 29887214). This has been reported as likely pathogenic by the InSiGHT consortium and as pathogenic by several laboratories. We currently consider this variant to be likely pathogenic.

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