ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1989+5G>A

dbSNP: rs267607878
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000705517 SCV000834517 pathogenic Hereditary nonpolyposis colorectal neoplasms 2025-01-06 criteria provided, single submitter clinical testing This sequence change falls in intron 17 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 Lynch syndrome (PMID: 34925852). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 581631). 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 17, but is expected to preserve the integrity of the reading-frame (PMID: 34925852). This variant disrupts the c.1989+5G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8993976, 14970868, 17473388). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001013923 SCV001174567 pathogenic Hereditary cancer-predisposing syndrome 2021-11-17 criteria provided, single submitter clinical testing The c.1989+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 17 in the MLH1 gene. This alteration has been identified in a proband that also had somatic MLH1 copy neutral loss of heterozygosity (CN-LOH) in a MSI-H colon tumor with loss of MLH1 and PMS2 expression by immunohistochemistry (IHC) where MLH1 promotor hypermethylation was negative (Ambry internal data). In addition, this alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in a MSI-H uterine tumor with loss of MLH1 and PMS2 expression by IHC where MLH1 promotor hypermethylation was negative (Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). 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.
Color Diagnostics, LLC DBA Color Health RCV001013923 SCV004359261 likely pathogenic Hereditary cancer-predisposing syndrome 2022-02-28 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of intron 17 of the MLH1 gene. Functional RNA studies have shown that this variant results in exon 17 skipping and an in-frame deletion of 93 nucleotides (DOI: 10.1093/gastro/goab030). This deletion potentially impacts the EXO1 and PMS2 binding domains (PMID: 11292842, 11427529). This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer (DOI: 10.1093/gastro/goab030). It has been shown that this variant segregates with disease, with multiple affected carriers in a single family (DOI: 10.1093/gastro/goab030). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, 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.