Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001186811 | SCV001353391 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-07-08 | criteria provided, single submitter | clinical testing | This variant causes a T>G nucleotide substitution at the +2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. |
Invitae | RCV001862943 | SCV002195521 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-04-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 15342696, 17312306, 27601186, Invitae). ClinVar contains an entry for this variant (Variation ID: 925072). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 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). |