ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.207+1G>A (rs267607718)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075505 SCV000106501 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000128866 SCV000172723 pathogenic Hereditary cancer-predisposing syndrome 2019-02-18 criteria provided, single submitter clinical testing The c.207+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MLH1 gene. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
Invitae RCV000627707 SCV000284045 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 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). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27978560, 16142001, Invitae). ClinVar contains an entry for this variant (Variation ID: 90020). 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.
GeneDx RCV000202020 SCV000568563 likely pathogenic not provided 2017-10-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.207+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the MLH1 gene. This variant destroys a canonical splice donor site and is predicted 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 several individuals with personal and/or family histories suggestive of Lynch syndrome (Mangold 2005, Lastella 2011, Laduca 2014, Pearlman 2017). Based on the currently available information, we consider MLH1 c.207+1G>A to be a likely pathogenic variant.
Color Health, Inc RCV000128866 SCV001340138 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202020 SCV000257084 likely pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000202020 SCV000592338 pathogenic not provided no assertion criteria provided clinical testing The c.207+1G>A variant has not been identified previously. The c.207+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant 1 and +2 positions region of the splice consensus sequence. Another variant at the same splice site (c.207+1G>T) has also been described to have splicing defect (Mangold 2005). In summary, based on the above information, this variant is classified as pathogenic.

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