Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000792147 | SCV000931425 | likely pathogenic | Fanconi anemia | 2019-05-01 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 6-23 of the FANCM gene. The 5' boundary is likely confined to intron 5. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. This variant has not been reported in the literature in individuals with FANCM-related conditions. This variant disrupts the C-terminal domain of the FANCM protein, including the entire ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs. These domains are critical for the interaction between FANCM and its DNA-binding partner FAAP24, as well as chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID: 17289582, 23932590, 18174376, 19379763, 24003026). While functional studies have not been performed to directly test the effect of this variant on FANCM protein function, this suggests that disruption of this region of the protein may be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |