ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1896+1G>T (rs267607867)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075405 SCV000106401 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000684807 SCV000543560 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 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 individuals affected with Lynch syndrome (LS) or clinical features of LS (PMID: 10533476, 15849733, 21642682, 12067992, Invitae). This variant is also described as a GAGgtg->GAGttg change in the splice donor site in the literature. ClinVar contains an entry for this variant (Variation ID: 89926). 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 RCV000479456 SCV000568570 likely pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1896+1G>T or IVS16+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 16 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 identified in several individuals suspected of having Lynch syndrome, including two whose tumors displayed microsatellite instability (MSI-H), with one also exhibiting loss of MLH1 protein expression on immunohistochemistry (IHC) (Nilbert 1999, Wahlberg 2002, Mangold 2005, Dymerska 2010, Bonadona 2011). Based on the currently available information, we consider MLH1 c.1896+1G>T to be a likely pathogenic variant.
Ambry Genetics RCV001013523 SCV001174121 pathogenic Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing The c.1896+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 16 of the MLH1 gene. This mutation has been detected in multiple individuals meeting Bethesda criteria whose tumors showed high microsatellite instability (Planck M et al. Int J Cancer. 1999 Oct 8;83(2):197-202; Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Nilbert M et al. Eur. J. Cancer, 1999 Jun;35:942-5), and in multiple individuals whose tumors were absent MLH1 and PMS2 on immunohistochemistry (Ambry internal data). 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.

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