ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.208-3C>G

dbSNP: rs267607720
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075517 SCV000106518 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration (not quantified) & 3 MSI-H tumours. Multifactorial likelihood analysis posterior probability 0.95-0.99.
GeneDx RCV000160554 SCV000211132 likely pathogenic not provided 2023-05-30 criteria provided, single submitter clinical testing Intronic variant demonstrated to result in an in-frame deletion of exon 3 (Arnold et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 26681312, 25980754, 28765196, 30787465, 29345684, 29887214, 31997046, 19267393, 15991306)
Invitae RCV000524274 SCV000284047 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-05-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (Deletion of Exon 3) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15991306, 19267393, 25980754). ClinVar contains an entry for this variant (Variation ID: 90032). This variant is also known as IVS2-3C>G. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15991306, 19267393, 26681312). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Ambry Genetics RCV000562969 SCV000669543 pathogenic Hereditary cancer-predisposing syndrome 2023-05-30 criteria provided, single submitter clinical testing The c.208-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 3 in the MLH1 gene. This alteration has been reported in multiple individuals with MLH1/PMS2-absent, microsatellite unstable, HNPCC-related tumors (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and analysis of patient-derived RNA found that this alteration results in aberrant splicing leading to transcripts lacking coding exon 3 (Otway R, Hum. Genet. 2005 May; 116(6):535; Arnold S, Hum. Mutat. 2009 May; 30(5):757-70). This alteration also co-segregates with HNPCC-related tumors in multiple families (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000075517 SCV000887397 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.208-3C>G has a 97.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics, Fulgent Genetics RCV000763098 SCV000893640 likely pathogenic Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2018-10-31 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003451102 SCV004188299 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-17 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160554 SCV004220869 likely pathogenic not provided 2023-05-19 criteria provided, single submitter clinical testing The MLH1 c.208-3C>G variant (also known as IVS2-3C>G) has been reported in the published literature in individuals and families affected with a Lynch syndrome associated cancer and/or polyps including colorectal cancer (PMID: 15991306 (2005), 19267393 (2009), 25980754 (2015), 26681312 (2015)). Functional studies report this variant results in the in-frame deletion of exon 3 (PMID: 15991306 (2005), 19267393 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, Based on the available information, this variant is classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.