Submissions for variant NM_003072.5(SMARCA4):c.656C>T (p.Thr219Met)

gnomAD frequency: 0.00004  dbSNP: rs371832808

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550755	SCV000648153	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-12-18	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). 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 SMARCA4 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	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. Jude Molecular Pathology, St. Jude Children's Research Hospital	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.
GeneDx	RCV001662574	SCV001872480	uncertain significance	not provided	2024-03-28	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-Nilou Lab	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