Table 1.
BRCA1 frameshift variants: Annotation and summary of results
| Frameshift variant (nt) | Classa | HGVS variant (aa) | Indel (nt) | Number of incorrect amino acid residuesb | Number of lost correct amino acid residuesc | dbSNP | ClinVard and review statuse | Number of entries in ClinVar | Number of observations in BRCA LOVDf | Allele frequency (gnomad) | This study |
|||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Number of observations (Ambry) | Number of families observed | TA VarCall fClassg | TA AMP/ACMG codeh | HR efficiencyi | HR AMP/ACMG codeh | |||||||||||
| c.5363dup | PPT | p.(Ala1789CysfsTer41) | G | 40 | 75 | – | – | – | 2 | – | – | – | 5 | PS3 | – | – |
| c.5464dup | PPT | p.(His1822ProfsTer8) | C | 7 | 42 | rs1567757816 | – | – | 2 | – | – | – | 5 | PS3 | – | – |
| c.5485dup | EIT | p.(Glu1829GlyfsTer51) | G | 50 | 35 | rs768401297 | P (3) | 2 | 6 | 0.000004 | – | – | 5 | PS3 | – | – |
| c.5507_5508del | EIT | p.(Glu1836ValfsTer43) | AG | 42 | 28 | – | – | – | 1 | – | – | – | 5 | PS3 | – | – |
| c.5511_5524del | EIT | p.(Trp1837CysfsTer38) | GGTGTTG GACAGTG |
37 | 27 | – | – | – | 1 | – | – | – | 5 | PS3 | – | – |
| c.5512dup | EIT | p.(Val1838GlyfsTer42) | G | 41 | 26 | – | – | – | 1 | – | – | – | 5 | PS3 | – | – |
| c.5530del | PPT | p.(Leu1844SerfsTer11) | C | 10 | 20 | – | P (n/r) | 1 | 3 | – | – | – | 5 | PS3 | – | – |
| c.5532_5533insG | EIT | p.(Tyr1845ValfsTer35) | G | 34 | 19 | rs397509293 | – | 1 | – | – | – | – | 5 | PS3 | – | – |
| c.5533_5540del | EIT | p.(Tyr1845ProfsTer32) | TACCAGTG | 31 | 19 | – | – | – | 1 | – | – | – | 5 | PS3 | – | – |
| c.5533dup | EIT | p.(Tyr1845LeufsTer35) | T | 34 | 19 | rs397509294 | P (3) | 4 | 2 | – | 1 | – | 5 | PS3 | – | – |
| c.5534del | PPT | p.(Tyr1845SerfsTer10) | A | 9 | 19 | rs1060505048 | P (3) | 3 | – | – | 1 | – | 5 | PS3 | Def. | PS3 |
| c.5542del | PPT | p.(Gln1848ArgfsTer7) | C | 6 | 16 | rs2152575457 | – | – | 1 | – | – | – | 5 | PS3 | – | – |
| c.5542dup | EIT | p.(Gln1848ProfsTer32) | C | 31 | 16 | – | – | – | – | – | – | – | 5 | PS3 | – | – |
| c.5553dup | EIT | p.(Thr1852HisfsTer28) | C | 27 | 12 | rs397509297 | P (3) | 1 | 2 | – | – | – | 5 | PS3 | – | – |
| c.5554_5558del | EIT | p.(Thr1852ProfsTer26) | ACCTA | 25 | 12 | rs1597796682 | P (1) | 1 | – | – | 1 | – | 5 | PS3 | – | – |
| c.5556dup | EIT | p.(Tyr1853LeufsTer27) | C | 26 | 11 | – | – | 1 | 2 | – | – | – | 5 | PS3 | – | – |
| c.5562del | EIT | p.(Ile1855TyrfsTer67) | G | 66 | 9 | rs886037795 | VUS (1) | 1 | – | – | – | – | 5 | PS3 | – | – |
| c.5563del AinsGGATTC |
EIT | p.(Ile1855GlyfsTer70) | delAins GGATTC |
68 | 9 | rs483353103 | conflict (1) | 2 | – | – | 1 | – | 5 | PS3 | – | – |
| c.5569del | EIT | p.(Gln1857ArgfsTer65) | C | 64 | 7 | rs886039675 | LP (2) | 4 | – | – | 2 | – | 5 | PS3 | – | – |
| c.5578dup | EIT | p.(His1860ProfsTer20) | C | 19 | 4 | rs397507254 | conflict (1) | 8 | 2 | – | 23 | 1 | 1 | BS3 | Prof. | BS3 |
| c.5578del | EIT | p.(His1860ThrfsTer62) | C | 61 | 4 | rs397507254 | LP (1) | 2 | – | – | – | 7 | 5 | PS3 | Def. | PS3 |
| c.5579_∗2del16 | EIT | p.(His1860ArgfsTer57) | ACAGCCA CTACTGAct |
56 | 4 | – | VUS (1) | 1 | – | – | 1 | – | 5 | PS3 | Def. | PS3 |
PPT (premature protein termination) variants used as (loss-of-function) pathogenic controls; EIT, extended incorrect terminus variants.
Number of incorrect amino acid residues downstream of reported mutation.
Number of correct amino acid residues lost downstream of reported mutation.
P, pathogenic; LP, likely pathogenic; conflict, conflicting interpretations; VUS, variant of uncertain significance.
ClinVar review status: 1 = criteria provided, single submitter; 2 = criteria provided multiple submitters; 3 = reviewed by expert panel; n/r, not reported; n/p, not provided.
LOVD, Leiden Open Variation database, obtained through BRCA Exchange.
TA VarCall functional classes: fClass 1 (nonpathogenic; PrDel ≤ 0.001), fClass 2 (likely not pathogenic; 0.001< PrDel ≤ 0.05), fClass 3 (uncertain; 0.05 > PrDel ≤ 0.95), fClass 4 (likely pathogenic; 0.95 < PrDel ≤ 0.99), and fClass 5 (pathogenic; PrDel > 0.99).
AMP/ACMG evidence strength codes: PS3, strong evidence for pathogenicity (odds of pathogenicity > 18.7); BS3, strong evidence for benignity (odds of pathogenicity <0.053); n/a, not applicable.
HR, homologous recombination; Prof., proficient; Def., deficient.