ClinVar

Description

This sequence change replaces lysine with threonine at codon 45 of the BRCA1 protein (p.Lys45Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. It also falls at the last nucleotide of exon 3 of the BRCA1 coding sequence. This variant is present in population databases (rs80356863, ExAC <0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 20104584) and in individuals in the Breast Cancer Information Core (BIC) database (PMID: 10923033). However, a pathogenic allele was identified in the BRCA2 gene, which suggests that this c.134A>C substitution in BRCA1 was not the primary cause of disease in one of the individuals in the BIC database. ClinVar contains an entry for this variant (Variation ID: 37402). Experimental studies have shown that this missense change disrupts ubiquitin ligase activity of the BRCA1/BARD1 heterodimer in vitro (PMID: 16403807). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this rare variant disrupts protein function in vitro and has been observed in affected individuals. However, it co-occurred with a pathogenic BRCA2 variant that likely explained one patient's condition. For these reasons, this change has been classified as a Variant of Uncertain Significance.