ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1409+1G>A (rs267607825)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075192 SCV000106182 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000220831 SCV000276156 pathogenic Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing The c.1409+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MLH1 gene. This mutation has been described in a Latvian individual with suspected HNPCC (Irmejs A et al. Anticancer Res. 2007;27(1):653-8) and has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at []). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct experimental evidence is unavailable. In addition, another mutation at the same nucleotide position, c.1409+1G>C, has been described in a Baltic/Polish individual fulfilling Amsterdam II criteria for HNPCC (Kurzawski G et al. J Med Genet. 2002;39:e65). 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, the c.1409+1G>A alteration is classified as a disease-causing mutation.
Invitae RCV000524237 SCV000543606 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in the literature in a family with suspected Lynch syndrome (PMID: 17348456). ClinVar contains an entry for this variant (Variation ID: 89718). A different variant affecting this nucleotide (c.1409+1G>C) has been determined to be pathogenic (PMID: 10200055, 12362047, 9322509, 14574010, 16451135). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000519388 SCV000617551 pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1409+1G>A or IVS12+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 12 of the MLH1 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one family withuterine and colorectal cancer (Irmejs 2007) and an alternate change, MLH1 c.1409+1G>C, has been observed in atleast one family meeting Amsterdam Criteria for Lynch syndrome (Peltomäki 1997, Kurzawski 2002). Based on thecurrent evidence, we consider MLH1 c.1409+1G>A to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075192 SCV000696109 likely pathogenic Lynch syndrome 2017-07-12 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1409+1G>A variant involves the alteration of a non-conserved intronic nucleotide that 5/5 splice prediction tools predict a the elimination of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 120470 control chromosomes. A publication cites the variant in an affected individual. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
GeneKor MSA RCV000519388 SCV000821733 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a substitution of the first nucleotide of intron 12 of the MLH1 gene. This position is highly conserved in human and other genomes. It is expected that this variant affects the correct mRNA splicing and results in the deletion of an entire exon. This causes the formation of a truncated non functional protein. This mutation has been described in international literature in families with suspected Lynch syndrome (PMID: 17348456).

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