Table 1.
Clinical, histopathological and molecular data of the ovarian cancer individuals heterozygous for the BRCA1/2 pathogenic variants.
| Case No. | Exon/Intron | Variant in Corresponding cDNA | Predicted Amino Acid Sequence | Variant Type | dbSNP ID 1 |
ACMG Classification 2 | Age, Years | FIGO Stage | Histology | Family History |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 (NM_007294.3; LRG_292t1) | ||||||||||
| M115 | 5 | c.181T>G | p.(Cys61Gly) | M | rs28897672 | Pathogenic (PS3 + PS4 + PM2 + PP1+ PP5) | 36 | IIIC | serous | - |
| M296 | 54 | IIIC | serous | + | ||||||
| K199 | 46 | IIIC | serous | - | ||||||
| K221 | 51 | IIIC | serous | - | ||||||
| D166 | 11 | c.676del | p.(Cys226Valfs*8) | F | rs80357941 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 43 | ND | serous | - |
| K187 | 11 | c.843_846del | p.(Ser282Tyrfs*15) | F | rs80357919 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 46 | IIIC | serous | - |
| D18 | 11 | c.1292dup | p.(Leu431Phefs*5) | F | rs80357528 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 42 | IIIC | serous | + |
| D138 | 11 | c.1687C>T | p.(Gln563*) | N | rs80356898 | Pathogenic (PVS1+PS4+PM1+PM2 + PP1 + PP5) | 49 | ND | serous | ND |
| K100 | 45 | IIB | serous | + | ||||||
| M397 | 11 | c.3296del | p.(Pro1099Leufs*10) | F | rs80357815 | Pathogenic (PVS1 + PM2 + PM4 + PP5) | 59 | IIIC | serous | ND |
| D53 | 11 | c.3626T>G | p.(Leu1209*) | N | rs786203884 | Pathogenic (PVS1 + PS4 + PM2 + PM4 + PP1 + PP5) | 59 | ND | low differentiated | ND |
| M22 | 11 | c.3700_3704del | p.(Val1234Glnfs*8) | F | rs80357609 | Pathogenic (PVS1 + PM1 + PM2 + PP5) | 61 | IIIB | serous | ND |
| M38 | 43 | IIIC | serous | - | ||||||
| M66 | 52 | ND | serous | ND | ||||||
| D3 | 45 | IIIC | serous | + | ||||||
| D23 | 47 | IV | serous | - | ||||||
| D63 | 55 | IIIC | serous | + | ||||||
| D70 | 48 | ND | serous | ND | ||||||
| D71 | 47 | ND | serous | - | ||||||
| D104 | 56 | ND | low differentiated | - | ||||||
| D136 | 43 | IIIB | serous | - | ||||||
| D156 | 47 | ND | serous | - | ||||||
| K65 | 64 | IIIC | serous | + | ||||||
| K125 | 50 | IIIC | serous | - | ||||||
| K152 | 66 | IV | serous | + | ||||||
| K189 | 63 | IIIC | low differentiated | + | ||||||
| K74 | 11 | c.3756_3759del | p.(Ser1253Argfs*10) | F | rs80357868 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 45 | IV | serous | + |
| D15 | 11 | c.4035del | p.(Glu1346Lysfs*20) | F | rs80357711 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 54 | IIB | serous | - |
| K222 | ND | IIB | low differentiated | + | ||||||
| M92 | 13 | c.4357+2T>G; r.[4186_4357del];[=] |
p.(Arg1377Tyrfs*2) | S | rs80358152 | Pathogenic (PVS1 + PS2 + PM2 + PP1 + PP3 + PP5) | 48 | IIIC | serous | + |
| M95 | 13 | 45 | IIIC | serous | - | |||||
| M395 | 14 | c.4484+1G>A; r.[4358_4484del];[=] | p.(Glu1462*) | S | rs80358063 | Pathogenic (PVS1 + PS3 + PP1 + PP3 + PP4 + PP5) | 41 | IIIC | serous | ND |
| K201 | 52 | IV | mesonephroid | + | ||||||
| D140 | 15 | c.4675G>A; r.[4665_4675del];[=] | p.(Glu1556Glyfs*13) | S | rs80356988 | Pathogenic (PS3 + PM1 + PM2 + PP1 + PP5) | 37 | IIIC | serous | ND |
| K73 K108 |
15 | c.4675+1G>A; r.[4485_4675del];[=] | p.(Ser1496Glyfs*14) | S | rs80358044 | Pathogenic (PVS1 + PS3 + PM1 + PM2 + PP1 + PP3 + PP5) | 44 41 |
IIIC IIIC |
serous clear cell |
ND - |
| D152 | 16 | c.4689C>G | p.(Tyr1563*) | N | rs80357433 | Pathogenic (PVS1 + PS4 + PM1 + PP1 + PP3 + PP4) | 38 | ND | serous | - |
| D72 | 16 | c.4986+6T>G, r.[4916+1_4916+65ins];[=] |
p.(Met1663Valfs*14) | S | rs80358086 | Pathogenic (PS3 + PS4 + PM1 + PM2 + PP1 + PP3 + PP5) | 47 | IIIC | serous | + |
| M50 | 20 | c.5266dup | p.(Gln1756Profs*74) | F | rs397507247 | Pathogenic (PVS1 + PM1 + PP5) | 52 | IIIC | serous | + |
| M108 | 63 | ND | serous | ND | ||||||
| M138 | 65 | ND | serous | + | ||||||
| M225 | 50 | IIID | serous | + | ||||||
| M226 | 51 | IIIC | serous | + | ||||||
| M227 | 58 | IIIC | serous | - | ||||||
| M314 | 46 | IIIC | endometrial | + | ||||||
| M323 | 37 | IIIC | serous | + | ||||||
| M368 | 60 | ND | serous | ND | ||||||
| M374 | 66 | ND | serous | ND | ||||||
| M378 | 36 | ND | serous | ND | ||||||
| D9 | 43 | IIIB | endometrial | + | ||||||
| D27 | 66 | IIIC | serous | ND | ||||||
| D66 | 47 | ND | serous | + | ||||||
| D83 | 50 | IIIC | serous | + | ||||||
| D99 | ND | IIIC | serous | ND | ||||||
| D105 | 50 | ND | serous | + | ||||||
| D144 | 56 | IIC | serous | ND | ||||||
| D149 | 40 | ND | serous | - | ||||||
| K53 | 60 | IIIC | serous | + | ||||||
| K121 | 52 | IIIB | clear cell | - | ||||||
| K197 | 43 | IIIC | endometrial | - | ||||||
| BRCA2(NM_000059.3; LRG_293t1) | ||||||||||
| M164 | 11 | c.2808_2811del | p.(Ala938Profs*21) | F | rs80359351 | Pathogenic (PVS1 + PS4 + PM2 + PP5) | 81 | ND | serous | + |
| D121 | 11 | c.3847_3848del | p.(Val1283Lysfs*2) | F | rs746229647 | Pathogenic (PVS1 + PM1 + PM2 + PP1 + PP5) | ND | ND | serous | ND |
| D114 | 11 | c.3860del | p.(Asn1287Ilefs*6) | F | rs80359406 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 54 | IIIC | serous | + |
| M8 | 11 | c.3975_3978dup | p.(Ala1327Cysfs*4) | F | rs764689249 | Pathogenic (PVS1 + PS4 + PM2 + PP5) | 45 | IV | serous | + |
| K183 | 56 | IV | low differentiated | + | ||||||
| K212 | 11 | c.4440T>G | p.(Tyr1480*) | N | rs397507719 | Pathogenic (PVS1 + PM1 + PM2 + PP1 + PP3 + PP5) | 54 | IIIC | serous | + |
| M178 | 11 | c.5042_5043del | p.(Val1681Glufs*7) | F | rs80359478 | Pathogenic (PVS1 + PS4 + PM1 + PM2 + PP1 + PP5) | 62 | IIIC | serous | - |
| D160 | 11 | c.5238dup | p.(Asn1747*) | F | rs80359499 | Pathogenic (PVS1 + PM1 + PM2 + PP1 + PP5) | 51 | IIIC | serous | - |
| K172 | 55 | IIIC | serous | - | ||||||
| K254 | 11 | c.5279C>A | p.(Ser1760*) | N | novel | Pathogenic (PVS1 + PM1 + PM2 + PP1 + PP3 + PP5) | ND | IV | mesonephroid | - |
| K93 | 11 | c.6393_6396del | p.(Lys2131Asnfs*5) | F | rs397507849 | Pathogenic (PVS1 + PM1 + PM2 + PP1 + PP5) | 76 | IIIC | serous | ND |
1 RS number based on the dbSNP Database (https://www.ncbi.nlm.nih.gov/projects/SNP/) (as of September 2018); 2 Interpretation of variants pathogenicity based on the American the College of Medical Genetics and Genomics (ACMG) recommendations [15], i.e., PVS1: null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of a disease, PS1: same amino acid change as a previously established pathogenic variant regardless of nucleotide change, PS2: proven de novo (both maternity and paternity confirmed), PS3: well-established functional studies, PS4: the prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls, PM1: located in a mutational hot spot and/or in critical functional domain, PM2: absent from controls, PM3: for recessive disorders, detected in trans with a pathogenic variant, PM4: protein length changes due to in-frame or stop-loss variants, PM5: novel missense change at amino acid residue where a different pathogenic missense change has been seen before, PM6: assumed de novo, but without confirmation of paternity and maternity, PP1: co-segregation with disease in multiple affected family members, PP2: missense variant in a gene that has a low rate of benign missense variation, PP3: multiple lines of computational evidence support a deleterious effect on the gene or gene product, PP4: individual’s phenotype or family history is highly specific for a disease, PP5: reputable source reports variant as pathogenic. To classify a variant as pathogenic the following criteria need to be fulfilled: ≥ 2 strong (PS1–PS4) OR 1 strong (PS1–PS4) and ≥3 moderate (PM1–PM6) OR 1 strong (PS1–PS4) and 2 moderate (PM1–PM6) and ≥2 supporting (PP1–PP5) OR 1 strong (PS1–PS4) and 1 moderate (PM1–PM6) and ≥4 supporting (PP1-PP5). Abbreviations: FIGO: International Federation of Gynecology and Obstetrics; ND: no data; F: frameshift; N: nonsense; S: splicing; M: missense.