Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001210948 | SCV001382464 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-09-18 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with Lynch syndrome (LS) or clinical features of LS (PMID: 12067992, 12658575, 15178966; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002356902 | SCV002653164 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-02-03 | criteria provided, single submitter | clinical testing | The c.589-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MLH1 gene. Another alteration impacting the same acceptor site (c.589-2A>G) has been shown to have a similar impact on splicing and has been reported in numerous Lynch syndrome families to date (Luce MC et al. Gastroenterology. 1995 Oct;109(4):1368-74; Viel A et al. Community Genet. 1998;1(4):229-36; Capozzi E et al. Eur. J. Cancer. 1999 Feb;35(2):289-95; Syngal S et al. JAMA. 1999 Jul 21;282(3):247-53; Casey G et al. JAMA. 2005 Feb 16;293(7):799-809; DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5(5):553-569), and RNA studies have demonstrated that the c.589-2A>G alteration activates a cryptic acceptor site resulting in a transcript with a 4 base pair deletion, which is predicted to lead to a translational frameshift (Ambry internal data; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Fulgent Genetics, |
RCV002497722 | SCV002811136 | likely pathogenic | Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 | 2022-02-11 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV003449664 | SCV004186497 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-17 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769]. |
| Baylor Genetics | RCV003449664 | SCV004190634 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-08-28 | criteria provided, single submitter | clinical testing |