Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000550755 | SCV000648153 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 219 of the SMARCA4 protein (p.Thr219Met). This variant is present in population databases (rs371832808, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470443). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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 | RCV000569280 | SCV000672189 | likely benign | Hereditary cancer-predisposing syndrome | 2021-10-07 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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. |
| St. |
RCV000550755 | SCV001775537 | likely benign | Rhabdoid tumor predisposition syndrome 2 | 2021-01-06 | criteria provided, single submitter | clinical testing | The SMARCA4 c.656C>T (p.Thr219Met) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v3.1 (https://gnomad.broadinstitute.org/variant/19-10986489-C-T). This population frequency is higher than expected for a pathogenic variant in SMARCA4 causing Rhabdoid Tumor Predisposition Syndrome (BS1). In silico tools predict a benign effect on the gene or protein function (BP4). This variant has been identified in two individuals without a personal or family history of rhabdoid tumors or Coffin-Siris syndrome (internal data). To our knowledge, this variant has not been reported in individuals with Rhabdoid Tumor Predisposition Syndrome. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4. |
| Gene |
RCV001662574 | SCV001872480 | uncertain significance | not provided | 2022-08-09 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Genome- |
RCV001809543 | SCV002057951 | likely benign | Intellectual disability, autosomal dominant 16 | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000550755 | SCV004204892 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2023-10-06 | criteria provided, single submitter | clinical testing |