ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.791-2A>G (rs267607794)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075863 SCV000106880 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
GeneDx RCV000212525 SCV000149395 pathogenic not provided 2021-08-16 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Reported in individuals with Lynch-related cancers with at least one tumor showing loss of MLH1 and PMS2 expression (Samowitz 2001, Sjursen 2010, Bonadona 2011); This variant is associated with the following publications: (PMID: 15331927, 11606497, 28152038, 26681312, 25525159, 12624141, 20587412, 21642682)
Ambry Genetics RCV000115486 SCV000213526 pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing The c.791-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 10 of the MLH1 gene. This alteration was reported in a 56 year old female diagnosed with colon cancer who had many first degree relatives affected with Lynch syndrome associated cancers; more than half of these family members were diagnosed before the age of 50 (Samowitz et al. Gastroenterology. 2001 Oct;121(4):830-8). This alteration was also reported in a Norwegian family that met Amsterdam criteria and had absent MLH1 and PMS2 staining on immunohistochemistry, as well as in a French family that met Amsterdam criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13; Sjursen et al. J Med Genet. 2010 Sep;47(9):579-85). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (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.
Invitae RCV000543128 SCV000625196 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 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 individuals and families affected with Lynch syndrome (PMID: 12624141, 20587412, 11606497, 21642682). This variant is also known as IVS9-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90372). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000115486 SCV000908614 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing

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