Submissions for variant NM_007294.4(BRCA1):c.3865A>C (p.Thr1289Pro)

dbSNP: rs1064795449

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483677	SCV000571259	uncertain significance	not provided	2016-08-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3865A>C at the cDNA level, p.Thr1289Pro (T1289P) at the protein level, and results in the change of a Threonine to a Proline (ACA>CCA). Using alternate nomenclature, this variant would be defined as BRCA1 3984A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr1289Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1289Pro occurs at a position that is not conserved and is located in the DNA Binding Domain as well as a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Thr1289Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002356784	SCV002622860	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-23	criteria provided, single submitter	clinical testing	The p.T1289P variant (also known as c.3865A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3865. The threonine at codon 1289 is replaced by proline, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is poorly 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 p.T1289P remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002356784	SCV003851091	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).