Submissions for variant NM_007294.4(BRCA1):c.878C>G (p.Thr293Ser)

gnomAD frequency: 0.00006  dbSNP: rs747172803

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691325	SCV000819101	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 293 of the BRCA1 protein (p.Thr293Ser). This variant is present in population databases (rs747172803, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 570469). 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) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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	RCV001018322	SCV001179546	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-27	criteria provided, single submitter	clinical testing	The p.T293S variant (also known as c.878C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 878. The threonine at codon 293 is replaced by serine, an amino acid with similar properties. This alteration has been reported in an ovarian cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas and was functional in a homology directed DNA repair (HDR) assay (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001018322	SCV001358884	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 293 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant has neutral impact on homology-directed repair activity in a cell-based assay (PMID: 26689913). This variant has been reported in an individual affected with ovarian cancer (PMID: 26689913). This variant has also been identified in 6/282616 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.
GeneDx	RCV001766481	SCV002000275	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: homology-directed repair activity similar to wild-type (PMID: 26689913); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 997C>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 20215511, 9582019, 9926942, 9788437, 15343273, 26689913, 37951914)
University of Washington Department of Laboratory Medicine, University of Washington	RCV001018322	SCV003847880	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV004802364	SCV005428637	uncertain significance	BRCA1-related cancer predisposition	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 293 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant has neutral impact on homology-directed repair activity in a cell-based assay (PMID: 26689913). This variant has been reported in an individual affected with ovarian cancer (PMID: 26689913). This variant has also been identified in 6/282616 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.