Table 1

Comprehensive analysis of BRCA1 variants

Exon	Mutation	Nucleotide change*	Allowed residues†	TXN‡	IV§	PDG¶	PS**	ST††	BIC‡‡	CO§§	Comments
Nucleotide numbering corresponds to human BRCA1* cDNA deposited in GenBank accession number U14680.
†Amino acid residues present at the same position in the BRCA1 orthologs. The multiple sequence alignment of orthologous BRCA1 BRCT domains from eight species, including Homo sapiens (GenBank accession number U14680), Pan troglodytes (AF207822), Mus musculus (U68174), Rattus norvegicus (AF036760), Gallus gallus (AF355273), Canis familiaris (U50709), Bos Taurus (AY077732), Xenopus laevis (AF416868), and Tetraodon nigroviridis (AY428536), was obtained by using program MegAlign (Clustal W).
‡Transcription assays.
§Interspecific variation.
¶Pedigree analysis.
*Protease sensitivity; data from Williams et al*.²⁵
††Structure based prediction; data from Mirkovic et al.²⁴
‡‡Number of times this variant has been reported to the BIC database as of August 2004.
§§Number of times this variant has been observed co-occurring with a known deleterious BRCA1 mutation in 40 000 samples (Myriad Genetics Laboratories). ¶¶According to prediction by the Paircoil scoring form (http://paircoil.lcs.mit.edu/cgi-bin/paircoil).⁴³
○, neutral/low clinical relevance; ░, moderate to low risk variant, ▓, deleterious/high risk variant.
nd, not determined; na, not applicable; ?, unclassified.
13	H1402Y	C4323T	HDYNK	○	○	nd	na	na	1	1	Reduces the probability to form coiled coil¶¶ structure from 0.936 to 0.532
13	L1407P	T4339C	L	•	?	nd	na	na	1	0	Conserved stretch; reduces the probability to form coiled coil¶¶ structure from 0.936 to 0.037
13	H1421Y	C4380T	HRK	○	?	nd	na	na	2	0	Reduces the probability to form coiled coil¶¶ structure from 0.936 to 0.650
15	S1512I	G4654T	SGCA	○	?	nd	na	na	50	14	Allele frequency comparable in control and in breast–ovarian cancer cases^{34 35}; clinical data favour classification as benign polymorphism
16	S1613G	A4956G	SNF	○	○	nd	na	na	33	371	Allele frequency comparable in control and breast–ovarian cancer cases^{2 14 36 37}; commonly found in the Japanese group used as controls³⁸; clinical data favour classification as benign polymorphism
16	M1628V	A5001G	MVSR	•	○	nd	na	na	4	0
16	M1628T	T5002C	MVSR	○	?	○	na	na	70	4	Commonly found in the Japanese group used as controls³⁸; clinical data favour classification as benign polymorphism
17	T1685I	C5173T	T	•	•	nd	nd	•	2	0	Found in a case with bilateral breast cancer at 41/46 y; her mother was disease-free, but grandmother and grandmother’s sister had breast cancer at 55 and 85 y, respectively
18	G1706A	G5236C	G	▒	•	▒	nd	nd	4	0
18	A1708E	C5242A	A	•	•	na	•	•	39	0	Known unfolding mutation³⁹; no detectable activity in transcription assays or small colony phenotype test.^{6 11 19} Found in a early onset breast tumour, the mutant allele (present in the germline) was absent in control population and was retained in the tumour.⁴⁰ Clinical data favour classification as deleterious mutation; was used as negative control in transcription assays
19	T1720A	A5277G	TIVS	▒	?	○	○	○	12	0
20	A1752P	G5373C	AS	•	?	nd	•	•	3	na
21	M1775R	T5443G	M	•	•	na	•	•	23	0	No detectable activity in transcription assays or small colony phenotype test.^{6 11 19} Found in a early onset breast tumour, the mutant allele (present in the germline) was absent in control population and was retained in the tumour.⁴⁰ Segregates with disease.¹⁴ Clinical data favour classification as deleterious mutation; was used as negative control in transcription assays
22	G1788V	G5482T	G	•	•	nd	•	•	15	0	Found in a bilateral breast and ovarian cancer case with family history⁴¹
23	V1809F	G5544T	VIL	•	?	•	▒	○	4	0
24	W1837R	T5628C	W	•	•	○	•	•	5	0	Found in an early onset breast cancer case. Proband’s father also had breast cancer and the mutation was found to segregate with disease⁴²
24	Y1853X	C5677A/G	Y	•	•	na	•	•	10	0	Truncating mutation that destabilises the BRCT domains.^{4 14} Clinical data favour classification as deleterious mutation; was used as negative control in transcription assays