Table 6.
BRCA1 and BRCA2 sequence variants reclassified as a consequence of updated prior probabilities of pathogenicity
| Gene | HGVS (nucleotide) | HGVS (amino acid) |
BIC | Motif Location |
Z-score Category |
Published Prior |
Splicing Prior |
Missense Prior |
Selected Prior |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | c.4479_4484+2dup † | N/A | IVS14+2ins8 | donor | Z < −2.0 | 0.26 | 0.97 | N/A | 0.97 |
| mRNA analysis: 8bp retention of intron 14 (Whiley et al 2011) | |||||||||
| BRCA1 | c.4868C>G | p.A1623G | A1623G |
de novo donor |
−2 ≤ z < 0 | 0.01 | 0.64* | 0.02 | 0.64 |
| mRNA analysis: 119bp deletion of exon 16, variant also present in wild-type transcripts (Walker et al 2010) | |||||||||
| BRCA1 | c.5278-14C>G | N/A | IVS20-14C>G | acceptor | Z > +0.5 | 0.26 | 0.04 | N/A | 0.04 |
| mRNA analysis: no aberration detected (Spearman et al 2008) | |||||||||
| BRCA1 | c.5467+5G>C | N/A | IVS23+5G>C | donor | −2 ≤ z < 0 | 0.26 | 0.34 | N/A | 0.34 |
| Exon 23 deletion (Whiley et al 2011) | |||||||||
| BRCA2 | c.632-16A>C | N/A | IVS7-16A>C | acceptor | Increased MES score |
0.26 | 0.04 | N/A | 0.04 |
| mRNA analysis: no aberration detected (Thomassen et al 2012) | |||||||||
| Gene | HGVS (nucleotide) | Published source of observational data |
Cosegregation Bayes score |
Pathology LR ¥ |
Co- occurrence LR |
Family History LR |
Published Posterior |
Recalculated Posterior |
IARC Class ¶ |
Class Description |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | c.4479_4484+2dup † | Whiley et al., 2011 | 0.95 | 2.58 | 1 | 1 | 0.46 | 0.988 | 4 | Likely pathogenic |
| BRCA1 | c.4868C>G | Walker et al., 2010 | 27.72 | 1.23 | 1.09 | 10.47 | 0.80 | 0.999 | 5 | Pathogenic |
| BRCA1 | c.5278-14C>G | Whiley et al., 2011 | 1 | 1 | 1.58 | 0.14 | 0.07 | 0.009 | 2 | Likely not pathogenic |
| BRCA1 | c.5467+5G>C | Whiley et al., 2011 | 0.73 | 0.18 | 1 | 1 | 0.045 | 0.063 | 3 | Uncertain |
| BRCA2 | c.632-16A>C | Thomassen et al., 2012 | 1 | 1 | 1.20 | 0.22 | 0.086 | 0.011 | 2 | Likely not pathogenic |
*
De novo prior upgraded to the next higher qualitative category because the z score is higher than that of the corresponding wild-type donor.
¥
Pathology likelihood ratios (LRs )based on breast tumour ER, grade or TN status and using revised estimates from Spurdle et al (in press). Cosegregation, co-occurrence and family history LRs are from the cited source of observational data.
¶
Class strata as described in Plon et al (2008).
†
This variant was originally reported as c.4484+2ins8; insertion is due to duplication of GGAAAGGT