ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.207+2T>C (rs267607722)

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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) RCV000075508 SCV000106503 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507560 SCV000601385 likely pathogenic not provided 2016-10-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000153 SCV001156638 pathogenic not specified 2019-05-06 criteria provided, single submitter clinical testing The MLH1 c.207+2T>C variant (rs267607722) is reported in the literature in several individuals with a confirmed or suspected diagnosis of Lynch syndrome (Becouarn 2005, Bonadona 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as likely pathogenic by several laboratories, including an expert panel, in ClinVar (Variation ID: 90023). This variant abolishes the canonical splice donor site of intron 2, which is likely to disrupt gene function. Based on available information, this variant is considered to be likely pathogenic. References: Becouarn Y et al. Value of microsatellite instability typing in detecting hereditary non-polyposis colorectal cancer. A prospective multicentric study by the Association Aquitaine Gastro. Gastroenterol Clin Biol. 2005 Jun-Jul;29(6-7):667-75. Bonadona V et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 Jun 8;305(22):2304-10.
Ambry Genetics RCV001014311 SCV001175005 pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing The c.207+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 2 in the MLH1 gene. This alteration has been detected in a patient diagnosed with colorectal cancer whose tumor showed loss of MLH1 protein expression by IHC and was MSI-L and whose family history met Amsterdam I criteria (Becouarn Y et al. Gastroenterol Clin Biol. 2005 Jun-Jul;29(6-7):667-75). 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.<u>​</u>
Invitae RCV001210840 SCV001382348 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-26 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 several individuals affected with Lynch syndrome (PMID: 16142001, 21642682, Invitae). This variant is also known as IVS2+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 90023). 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.

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