Table 1.

Structure-based analysis of BRCA1 variants in the BRCT domains.

CLASS	VARIANT	NOTES
Hydrophobic core disruption	V1833M	V1833 in BRCT-C is completely inaccessible to solvent. It lies in the β4 strand, an edge strand of a four-stranded parallel beta sheet. The sidechain points inward towards the protein core. Valine is a β-branched residue that is more favored in β-strands than methionine and methionine is larger than valine, so this replacement likely disrupts the tight packing in the domain’s hydrophobic core.
No Evidence for Functional Impact	Q1826H	Q1826 in BRCT-C is on the protein surface and its sidechain points outward to the solvent. There are no known or predicting binding interactions at this position.
	M1652I	M1652 in BRCT-N is completely inaccessible to solvent. It lies in the β1 strand, an interior strand of a four-stranded parallel β-sheet. Isoleucine is a hydrophobic, β-branched residue that is more favored in β-strands than methionine. We expect that this replacement is benign with respect to BRCT function and may even have a protective, stabilizing effect in the presence of other destabilizing mutations.