Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV000773814 | SCV000907514 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-31 | criteria provided, single submitter | clinical testing | This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the SMAD4 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 a disrupted protein product via in-frame deletion. However, the functional impact of this is unclear. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice donor site, c.787+2T>C, is known to cause in-frame exon skipping and classified to be disease-causing (ClinVar variation ID: 851605). Loss of SMAD4 function is a known mechanism of disease. Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002406694 | SCV002680851 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2022-08-25 | criteria provided, single submitter | clinical testing | The c.787+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the SMAD4 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV002534098 | SCV003001294 | likely pathogenic | Juvenile polyposis syndrome | 2023-09-20 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 of the SMAD4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 629125). Studies have shown that disruption of this splice site results in skipping of 6, but is expected to preserve the integrity of the reading-frame (Invitae). 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. |