Submissions for variant NM_007294.3(BRCA1):c.5531T>C (p.Leu1844Pro) (rs80357323)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484935	SCV000567730	uncertain significance	not provided	2015-08-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5531T>C at the cDNA level, p.Leu1844Pro (L1844P) at the protein level, and results in the change of a Leucine to a Proline (CTC>CCC). Using alternate nomenclature, this variant would be defined as BRCA1 5650T>C. One functional study demonstrated reduced transcriptional activity compared to wild-type but significantly higher than that of mutant controls, leading the authors to classify BRCA1 Leu1844Pro as uncertain (Carvalho 2014). BRCA1 Leu1844Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Leu1844Pro occurs at a position that is not conserved and is located in the BRCT 2 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1844Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.