Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2using five methods: results from a population-based study of young breast cancer patients

Table 1 Mean Grantham matrix score of BRCA1/BRCA2 variants (unclassified variants) according to classification using allele frequency, Polyphen, and sequence conservation

Gene	Classification method	Level	Number of variants	Grantham matrix score
				Mean	Standard deviation	Minimum	Maximum
BRCA1	Allele frequency	Low risk (HFUV)	5	38.2	20.7	10	56
		High risk (LFUV)	39	69.7	45.0	10	194
		P value (t test)		0.13
	Polyphen	Benign missense	28	55.0	42.3	10	180
		Possible damaging	9	65.3	29.4	10	101
		Probably damaging	7	111.9	40.5	71	194
		P for trend^a		0.002
	Sequence conservation	Low	14	53.6	44.7	10	180
		Moderate	14	70.9	43.5	10	154
		High	16	73.0	44.2	10	194
		P for trend^a		0.24
BRCA2	Allele frequency	Low risk (HFUV)	18	67.7	39.7	5	149
		High risk (LFUV)	77	87.0	52.9	10	205
		P value (t test)		0.15
	Polyphen	Benign missense	44	58.1	41.3	5	194
		Possible-damaging	25	91.4	41.7	21	180
		Probably-damaging	26	118.3	52.3	27	205
		P for trend^a		<0.001
	Sequence conservation	Low	33	71.5	49.4	10	194
		Moderate	29	92.1	55.6	5	205
		High	33	87.5	47.8	21	194
		P for trend^a		0.20

LFUV, low-frequency unclassified variant; HFUV, high-frequency unclassified variant. ^aBased on the F test in a linear regression model.

ISSN: 1465-542X