A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2genes based on cancer family history

Table 2 The unclassified variants in the present study: epidemiological and biochemical criteria

Variant [22]	Number of families	Co-segregation (present study)^a	Polarity change	Conserved mammals/other [21]^b	Grantham score [19]	Times reported (Breast Cancer Information Core [1])	Co-segregation (literature)	Co-occurrence (literature)	Classification (literature)	Reference^c
BRCA1
p.L246V	2	ND	No	No/No	32	79	No	Yes (several)	Neutral	[5, 7, 13]
p.S1655F	2	6/6 (n = 2)	Yes	Yes/Yes	155	3	Not done	Not done	Deleterious	[5, 32, 34, 35]
p.R1699W	9	8/8 (n = 4)	Yes	Yes/Yes	101	13	Not done	No	Deleterious	[1, 14, 35]
p.R1699Q	5	1/2 (n = 2)^d	Yes	Yes/Yes	43	11	Yes	No	Deleterious, uncertain, low/moderate	[5, 6, 9, 12, 32, 34, 35]
Total	18
BRCA2
p.Y42C	3	ND	N	No/No	194	14	No	Yes	Neutral	[6, 9, 11]
p.E462G	8	2/5 (n = 5)	Yes	Yes/No	98	35	No	Yes (Y3097X)	Neutral	[11, 12]
p.Y2660D	9	8/8 (n = 5)	Yes	Yes/Yes	160	2	Not done	Not done		None
p.R2784W	1	ND	Yes	Yes/Yes	101	5	Not done	Not done	Uncertain	[33]
p.R2784Q	4	1/2 (n = 2)^e	Yes	Yes/Yes	43	4	Not done	Not done		None
p.R2888C	5	1/1 (n = 1)	Yes	No/Yes	180	4	No	Yes	Neutral	[14]
p.R3052W	10	1/1 (n = 1)	Yes	Yes/Yes	101	8	Not done	Not done	Deleterious	[33]
p.R3052Q	1	0/1 (n = 1)	Yes	Yes/Yes	43	3	Not done	Yes	Neutral	[14]
Total	41

^aCo-segregation in the present study is expressed as number of tested positive (proband excluded)/total number of affected relatives tested (n = number of families tested). ^bAlignments based on the following species and NCBI reference sequences: BRCA1: human (NP_009225), chimp (AAG43492), gorilla (AAT44835), orang (AAT44834), macacque (AAT44833), dog (AAC48663), mouse (AAD00168), cow (NP848668), opossum (AAX92675), chicken (NP989500), xenopus (AAL13037), and pufferfish (AAR89523); and BRCA2: human (NP000050), chimp (XP509619), dog (BAB91245), mouse (AAB48306), chicken (AAL89470), and tetraodon (CAG09009). ^cFunctional studies were performed in [11, 12, 32–35]. ^dLack of co-segregation was observed in one of the two pedigrees analyzed. In that pedigree, the proband had BC at age 37, her father's sister had BC at age 61, her cousin (the daughter of that aunt) had BC at age 45 – did not have the UV. ^eThis UV does not co-segregate with the disease in one family, which consisted of two affected members: the proband had BC at age 31, her mother with BC at age 67 – did not have the UV.

ISSN: 1465-542X