Submissions for variant NM_003072.5(SMARCA4):c.679G>A (p.Ala227Thr)

dbSNP: rs769096295

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458108	SCV000548382	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 227 of the SMARCA4 protein (p.Ala227Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMARCA4-related conditions (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 408603). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV000574449	SCV000663992	likely benign	Hereditary cancer-predisposing syndrome	2021-09-02	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.
Baylor Genetics	RCV001331670	SCV001523764	uncertain significance	Intellectual disability, autosomal dominant 16	2019-01-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001331670	SCV002056334	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000458108	SCV004204924	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2023-08-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477959	SCV004221246	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000066 (1/152210 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been identified in an individual with advanced cancer (PMID: 28873162 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.