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

dbSNP: rs267607720

Total submissions: 8

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524274	SCV000284047	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-07-24	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (gnomAD no frequency). 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. Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. This variant is also known as IVS2-3C>G. ClinVar contains an entry for this variant (Variation ID: 90032). 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; Invitae). 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. For these reasons, this variant has been classified as Pathogenic.
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, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.