ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-11C>T (rs776898290)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588982 SCV000570101 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-11C>T, and describes a nucleotide substitution 11 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is TCTT[C/T]TGGC. This variant has been observed in at least three individuals with colon cancer whose tumors demonstrated microsatellite instability (MSI-H) and/or absence of MLH1 expression by immunohistochemistry (IHC). While one of these individuals' tumors was also positive for MLH1 promoter hypermethylation, the other two were not (Hampel 2008. Ward 2013). MLH1 c.-11C>T has been reported to reduce promoter activity compared to wild type (Ward 2013). MLH1 c.-11C>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is not conserved. This variant does not appear to affect the start codon or the Kozak translational consensus sequence, and is not predicted to affect splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MLH1 c.-11C>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588982 SCV000696100 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.-11C>T variant involves the alteration of a non-conserved nucleotide located in the 5'UTR. Mutation Taster predicts a benign outcome for this variant. This variant is absent in 121940 control chromosomes including broad and large population from ExAC. This variant has previously been reported in two colon cancer patients, one with both MSI and MLHI IHC negative tumor, the other with either MSI or MLH1 IHC negative tumor, consistent with disease-causing outcome of the variant (Ward_2013). This report also performed functional studies in which c.-11C>T showed a significant reduction in promoter activity as compared with the wild-type promoter sequence (~49% and ~62% of wild-type activity in HCT116 and HEK293 cells, respectively). Taken together, this variant is currently classified as VUS-possibly pathogenic.
Color RCV000774690 SCV000908598 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing
Invitae RCV001057484 SCV001221981 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-30 criteria provided, single submitter clinical testing This variant occurs in a non-coding region of the MLH1 gene. It does not change the encoded amino acid sequence of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with colorectal cancer (PMID: 22878509, 18809606). ClinVar contains an entry for this variant (Variation ID: 421030). Experimental studies have shown that this variant reduces the promoter activity of MLH1 (PMID: 22878509). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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