Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000217621 | SCV000279065 | uncertain significance | not provided | 2017-12-07 | criteria provided, single submitter | clinical testing | This variant is denoted MLH1 c.-33T>G, and describes a nucleotide substitution 33 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 AGCA[T/G]CTAG. MLH1 c.-33T>G was identified along with a pathogenic MSH2 variant in an individual with an MSI-high colorectal cancer with absent expression of the MSH2 and MSH6 proteins (Hampel 2008). Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome, and variants located within the MLH1 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2009, Ward 2013). MLH1 c.-33T>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). The thymine (T) nucleotide that is altered is not conserved. Based on currently available evidence, we consider MLH1 c.-33T>G to be a variant of uncertain significance. |
Prevention |
RCV003891797 | SCV000805936 | uncertain significance | MLH1-related condition | 2023-12-26 | criteria provided, single submitter | clinical testing | The MLH1 c.-33T>G variant is located in the 5' untranslated region. This variant has been reported as a variant of uncertain significance in a patient with Lynch syndrome in a screen for causal MLH1 promoter and cis regulatory elements (Morak et al. 2018. PubMed ID: 29472279). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD, which may be too common to be a primary cause of disease. In ClinVar, it is interpreted as uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/234367/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Invitae | RCV001455878 | SCV001659645 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2022-03-26 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV002256127 | SCV002528739 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-19 | criteria provided, single submitter | curation |