Submissions for variant NM_007294.3(BRCA1):c.4015G>A (p.Glu1339Lys) (rs80357021)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159985	SCV000210163	uncertain significance	not provided	2014-08-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4015G>A at the cDNA level, p.Glu1339Lys (E1339K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1339Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1339Lys occurs at a position that is well conserved across mammals and is located within the SQ/TQ cluster domain (SCD), a region with preferred sites of phosphorylation by the ATM protein as well as the region of interaction with ATM, CHK2 and CDK2 (Narod 2004, Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Glu1339Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.