Submissions for variant NM_007294.4(BRCA1):c.3586A>T (p.Thr1196Ser)

dbSNP: rs1340335862

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509705	SCV000608098	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-28	criteria provided, single submitter	clinical testing	The p.T1196S variant (also known as c.3586A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3586. The threonine at codon 1196 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709475	SCV000953923	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-27	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 1196 of the BRCA1 protein (p.Thr1196Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 441435). 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 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.
Mendelics	RCV000989890	SCV001140552	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000509705	SCV002538218	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509705	SCV003848359	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	RCV000989890	SCV004817786	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 1196 of the BRCA1 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 BRCA1-related disorders in the literature. This variant has not been identified 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.