Additional Table 2. BRCA1 variants.
| Exon | HGVS Nucleotide | HGVS Protein | Protein | Other names | Type | Localization (GRCh37) | NCBI 1000 Genomes Browser | Global MAF dbSNP | Allele Frequency ExAC | Global MAF 1000 genomes | ESP | gnomAD | TOPMed | ABraOM | SIFT | PolyPhen | Provean | Align-GVGD (Pufferfish) | Human Splicing Finder | BRCA Exchange | BRCA Mutation Database | BRCA Share™ | ClinVar | Interpretation | n |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.-19-115T>C | - | - | IVS1-115T>C | 5'UTR | 17: 41276247 | rs3765640 | 0.35363 (G) | - | 0,35363 | - | 0,31688 | 0,30248 | 0.304260 | - | - | - | - | Mutant type not implemented in HSF yet | Benign / Little Clinical Significance | ND | ND | Benign | Benign | 9 |
| 2 | c.81-14C>T | - | - | IVS2-14C>T | IVS | 17: 41267810 | rs80358006 | - | - | - | 0.00069 | - | 0,00052 | 0.001642 | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign/Likely Benign | Benign/Likely Benign | 1 |
| 3 | c.134+111C>T | - | - | IVS3+111C>T | IVS | 17: 41267632 | rs8176100 | 0.00379 (A) | - | 0,00379 | - | 0,00227 | 0.00128 | - | - | - | - | - | Creation of an intronic ESE site. Probably no impact on splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 1 |
| 6 | c.301+43A>G | - | - | IVS6+43A>G | IVS | 17: 41256841 | - | - | - | - | - | - | - | - | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | ND | ND | ND | ND | Uncertain Significance | 1 |
| 7 | c.441+36_441+49delCTTTTCTTTTTTTT | - | - | IVS7+36del14 | IVS | 17: 41256090_41256103 | rs373413425 | - | - | - | - | - | - | 0.295230 | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Not Yet Reviewed | ND | 1-Neutral | Benign | Benign | 23 |
| 7 | c.441+36C>T | - | - | IVS7+36C>T | IVS | 17: 41256103 | rs45569832 | - | - | - | - | 0,00009 | - | - | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Not Yet Reviewed | ND | 3-UV | Uncertain significance? | Uncertain Significance | 2 |
| 7 | c.441+41C>T | - | - | IVS7+41C>T | IVS | 17: 41256098 | rs45489593 | - | 0,00024 | - | - | 0,00104 | - | - | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Not Yet Reviewed | ND | 1-Neutral | Uncertain significance? | Uncertain Significance | 1 |
| 7 | c.442-34C>T | - | - | IVS7-34C>T | IVS | 17: 41251931 | rs799923 | 0.09864 (A) | 0,17379 | 0,09864 | 0,17569 | 0,17303 | 0,14802 | 0.200328 | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Not Yet Reviewed | ND | 1-Neutral | Benign | Benign | 15 |
| 9 | c.548-58delT | - | - | c.IVS8-58delT | IVS | 17: 41249364 | rs8176144 | 0.33486 (AAAAAA) | - | - | 0,27833 | 0.3005 | 0,28382 | - | - | - | - | - | Alteration of an intronic ESS site. Probably no impact on splicing. | ND | ND | 1-Neutral | Benign | Benign | 2 |
| 9 | c.591C>T | p.Cys197= | C197= | 710C>T | Syn | 17: 41249263 | rs1799965 | 0.00040 (A) | 0,00147 | 0.00040 | 0,00123 | 0,00178 | 0,00076 | - | - | - | Neutral | - | Activation of an exonic cryptic donor site. Creation of an exonic ESS site. Potential alteration of splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 1 |
| 11 | c.1067A>G | p.Gln356Arg | Q356R | 1186A>G | M | 17: 41246481 | rs1799950 | 0.02177 (C ) | 0,04407 | 0,02177 | 0,0459 | 0,05196 | 0,04129 | 0.049261 | Deleterious (0.01) | Probably Damaging (0.988) | Deleterious | Class C0 | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 6 |
| 11 | c.1971A>G | p.Gln657= | Q657= | 2090 A>G | Syn | 17: 41245577 | rs28897679 | 0.00639 (C) | 0,00217 | 0,00639 | 0,00869 | 0,00605 | 0,00741 | 0.005747 | - | - | Neutral | - | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 1 |
| 11 | c.2077G>A | p.Asp693Asn | D693N | 2196G>A | M | 17: 41245471 | rs4986850 | 0.03355 (T) | 0.05681 | 0,03355 | 0,05429 | 0.05451 | 0.05336 | 0.056650 | Tolerated (0.08) | Benign (0.01) | Neutral | Class C0 | Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 9 |
| 11 | c.2082C>T | p.Ser694= | S694= | 2201C>T | Syn | 17: 41245466 | rs1799949 | 0.33646 (A) | 0,34827 | 0,33646 | 0,29568 | 0,31633 | 0,30145 | 0.302956 | - | - | Neutral | - | Activation of an exonic cryptic donor site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 22 |
| 11 | c.2311T>C | p.Leu771= | L771L | 2430T>C | Syn | 17: 41245237 | rs16940 | 0.33526 (G) | 0,34196 | 0,33526 | 0,27764 | 0,30018 | 0,28384 | 0.282430 | - | - | Neutral | - | Creation of an exonic ESS site. Potential alteration of splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 22 |
| 11 | c.2596C>T | p.Arg866Cys | R866C | 2715C>T | M | 17: 41244952 | rs41286300 | - | 0,0001 | - | - | 0,00016 | 0,00017 | - | Deleterious (0) | Probably Damaging (1) | Deleterious | Class C65 | Creation of an exonic ESS site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 1 |
| 11 | c.2612C>T | p.Pro871Leu | P871L | 2731C>T | M | 17: 41244936 | rs799917 | 0.45607 (G) | 0,41005 | 0,54393 | 0,49316 | - | 0,4893 | 0.450739 | Tolerated (1) | Benign (0) | Neutral | Class C0 | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 26 |
| 11 | c.3113A>G | p.Glu1038Gly | E1038G | 3232A>G | M | 17: 41244435 | rs16941 | 0.33566 (C) | 0,34287 | 0,33566 | 0,27903 | 0,30081 | 0,28456 | 0.282430 | Tolerated (0.16) | Possibly Damaging (0.606) | Deleterious | Class C0 | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 22 |
| 11 | c.3119G>A | p.Ser1040Asn | S1040N | 3238G>A | M | 17: 41244429 | rs4986852 | 0.00978 (T) | 0.00978 (T) | 0,00978 | - | 0,01109 | 0,01571 | 0.035304 | Tolerated (0.21) | Possibly Damaging (0.831) | Neutral | Class C0 | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 5 |
| 11 | c.3305A>G | p.Asn1102Ser | N1102S | - | M | 17: 41244243 | rs80356900 | - | 0,00002 | - | 0,00008 | 0,00001 | 0,00001 | - | Tolerated (0.17) | Benign (0.156) | Deleterious | Class C0 | Creation of an exonic ESS site. Potential alteration of splicing. | Not Yet Reviewed | 2-Likely not pathogenic or of little clinical significance | 3-UV | Uncertain significance? | Uncertain Significance | 1 |
| 11 | c.3548A>G | p.Lys1183Arg | K1183R | 3667A>G | M | 17: 41244000 | rs16942 | 0.35264 (C) | 0,34901 | 0,35264 | 0,29525 | 0,31548 | 0,30133 | 0.299672 | Tolerated (1) | Benign (0) | Neutral | Class C0 | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 22 |
| 11 | c.3752G>A | p.Cys1251Tyr | C1251Y | - | M | 17: 41243796 | rs879254079 | - | - | - | - | - | - | - | Tolerated (1) | Benign (0.001) | Neutral | Class C0 | Alteration of an exonic ESE site. Potential alteration of splicing. | Not Yet Reviewed | ND | ND | Uncertain significance? | Uncertain Significance | 1 |
| 11 | c.4039A>G | p.Arg1347Gly | R1347G | 4158A>G | M | 17: 41243509 | rs28897689 | 0.00060 (C) | 0.00398 | 0,0006 | 0,00484 | 0,00423 | 0,00481 | 0.005747 | Tolerated (0.09) | Benign (0.071) | Neutral | Class C0 | Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 2 |
| 12 | c.4113G>A | p.Gly1371= | G1371= | - | Syn | 17: 41243033 | rs147448807 | 0.00160 (T) | 0.00050 | 0,0016 | 0,00123 | 0,00156 | - | - | - | - | Neutral | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Likely benign | ND | 2-Likely Neutral | Likely Benign | Likely Benign | 1 |
| 13 | c.4308T>C | p.Ser1436= | S1436= | 4427T>C | Syn | 17: 41234470 | rs1060915 | 0.33626 (G) | 0,3431 | 0,33626 | 0,27956 | 0,30142 | 0,28489 | 0.283251 | - | - | Neutral | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 22 |
| 15 | c.4485-63C>G | - | - | IVS 14-63C>G | IVS | 17: 41226601 | rs273900734 | 0.35344 (C) | - | 0,35344 | - | 0,31645 | 0,30211 | 0.300493 | - | - | - | - | - | Benign / Little Clinical Significance | ND | ND | Benign | Benign | 2 |
| 16 | c.4837A>G | p.Ser1613Gly | S1613G | 4956A>G | M | 17: 41223094 | rs1799966 | 0.35583 (C) | - | 0,35583 | 0,29817 | - | 0,30333 | 0.300987 | Tolerated (0.11) | Benign (0.038) | Neutral | Class C0 | Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | 1-Not pathogenic or of no clinical significance | 1-Neutral | Benign | Benign | 22 |
| 16 | c.4987-92A>G | - | - | IVS16-92A>G | IVS | 17: 41219804 | rs8176233 | 0.35463 (C) | - | 0,35463 | - | 0,31276 | 0,30294 | 0.300493 | - | - | - | - | Alteration of an exonic ESE site. Potential alteration of splicing.- | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 3 |
| 16 | c.4987-68A>G | - | - | VS16-68A>G | IVS | 17: 41219780 | rs8176234 | 0.35463 (C) | - | 0,35463 | - | 0,31483 | 0,30295 | 0.301314 | - | - | - | - | Alteration of an exonic ESE site. Potential alteration of splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 3 |
| 17 | c.5074+2T>C | - | - | IVS17+2T>C | SS | 17: 41219623 | rs80358089 | - | - | - | - | - | - | - | - | - | - | - | Alteration of the WT donor site, most probably affecting splicing | Pathogenic | 5-Definitely pathogenic | ND | Pathogenic? | Pathogenic | 1 |
| 17 | c.5075-53C>T | - | - | IVS17-53C>T | IVS | 17: 41216021 | rs8176258 | 0.01098 (A) | - | 0,01098 | 0,01708 | 0,01825 | 0,01721 | 0.018062 | - | - | - | - | Alteration of an intronic ESS site. Probably no impact on splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 2 |
| 18 | c.5123C>A | p.Ala1708Glu | A1708E | 5242C>A | M | 17: 41215920 | rs28897696 | - | 0,02487 | - | 0.00023 (T) | - | - | - | Deleterious (0) | Possibly Damaging (0.633) | Neutral | Class C65 | Activation of an exonic cryptic acceptor site, with presence of one or more cryptic branch point(s). Creation of an exonic ESS site. Alteration of an exonic ESE site. Potential alteration of splicing. | Pathogenic | 5-Definitely pathogenic | 5-Causal | Pathogenic? | Pathogenic? | 1 |
| 18 | c.5152+66G>A | - | - | IVS18+66G>A | IVS | 17: 41215825 | rs3092994 | 0.34245 (T) | - | 0,34245 | - | 0,31394 | 0,29599 | 0.291461 | - | - | - | - | No significant splicing motif alteration detected. This mutation has probably no impact on splicing. | Benign / Little Clinical Significance | ND | 1-Neutral | Benign | Benign | 3 |
| 21 | c.5304C>T | p.Cys1768= | C1769C | - | M | 17: 41203108 | rs138493864 | 0.00060 (A) | 0.00002 | 0,0006 | 0,00015 | 0,00013 | 0,00009 | - | - | - | Neutral | - | Creation of an exonic ESS site. Potential alteration of splicing. | Likely benign | ND | ND | Likely Benign | Likely Benign | 1 |
HGVS: Human Genome Variation Society; MAF: Minor allele frequency; ESP: NHLBI Exome Sequencing Project Exome Variant Server; gnomAD: The Genome Aggregation Database; TOPMed: Trans-Omics for Precision Medicine; ABraOM: Brazilian genomic variants; SIFT: Sorting intolerant from tolerant; PolyPhen: Polymorphism Phenotyping; Provean: Protein Variation Effect Analyzer; Align-GVGD: Class C0 (less probable to interfere with protein function), C15, C25, C35, C45, C55, C65 (more probable to interfere with protein function); Syn: Synonymous; IVS: Intervening sequence; M: Missense; SS: splice site; ND, Not determined; n: Number of patients harboring the variant