ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1668-1G>A (rs267607845)

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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) RCV000075300 SCV000106296 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
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.
Ambry Genetics RCV000214110 SCV000278026 pathogenic Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing The c.1668-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the MLH1 gene. This alteration has been previously reported in several individuals with colorectal cancers demonstrating microsatellite instability and absent MLH1 and/or PMS2 IHC staining, including individuals meeting Amsterdam criteria (Taylor CF, et al. Hum. Mutat. 2003 Dec; 22(6):428-33; Piñol V, et al. JAMA 2005 Apr; 293(16):1986-94; Lamberti C, et al. Digestion 2006 ; 74(1):58-67; Pérez-Carbonell L, et al. Gut 2012 Jun; 61(6):865-72; Walker M et al. Br J Surg, 2007 Dec;94:1567-71). One splicing assay using cell lines from mutation carriers found that this alteration results in out-of-frame skipping of exon 15 (Arnold S, et al. Hum. Mutat. 2009 May; 30(5):757-70). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Health, Inc RCV000214110 SCV000684764 pathogenic Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000075300 SCV000731290 pathogenic Lynch syndrome 2019-04-19 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, Pérez-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 sequence and has been observed to cause altered splicing leading to an abnormal or absent protein (Arnold 2009, Pérez-Carbonell 2012). Heterozygous loss of function of the MLH1 gene is an established disease mechanism in Lynch Syndrome. Additionally, this variant has been classified as Likely pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT panel (ClinVar SCV000106296.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP criteria applied: PM2, PS4_Supporting, PVS1.
Invitae RCV000629693 SCV000750649 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-01 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.
Academic Department of Medical Genetics, University of Cambridge RCV000214110 SCV000992193 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353428 SCV000592416 uncertain significance not provided no assertion criteria provided clinical testing

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