Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000227385 | SCV000288877 | uncertain significance | Juvenile polyposis syndrome | 2024-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 185 of the SMAD4 protein (p.Pro185Leu). This variant is present in population databases (rs770798845, gnomAD 0.02%). 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: 240150). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002311352 | SCV000671995 | benign | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2023-08-23 | criteria provided, single submitter | clinical testing | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Color Diagnostics, |
RCV000572439 | SCV000910017 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-13 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 185 in the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has been identified in 4/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV003475828 | SCV004202584 | uncertain significance | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 2023-08-24 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479073 | SCV004223744 | uncertain significance | not specified | 2023-11-13 | criteria provided, single submitter | clinical testing | Variant summary: SMAD4 c.554C>T (p.Pro185Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.554C>T has been reported in the literature in multiple non-cancer control cohorts (e.g. Youssef_2017, Okawa_2023) and in at least one individual at high risk for breast/ovarian cancer (e.g. Kwong_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32068069, 36243179, 28199989). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| All of Us Research Program, |
RCV003475828 | SCV004820027 | uncertain significance | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing |