NM_007294.4:c.2998_3003del is an in-frame deletion of 6 nucleotides in BRCA1 exon 10 resulting in deletion of two glutamic acid residues at positions 1000-1001 (p.Glu1000_Glu1001del). This is not a null variant; PVS1 does not apply.1 The variant is present in gnomAD at low frequency: 5/282,204 alleles in v2.1 (AF=0.00177%) and 64/1,613,982 alleles in v4.1 (AF=0.00397%), with a maximum filter allele frequency of 0.0041%. This meets ENIGMA BS1_Supporting (FAF >0.002% and ≤0.01%).2 The deletion is located at amino acid positions 1000-1001, outside the three ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.01). This meets ENIGMA BP1_Strong for an in-frame deletion outside functional domains with no splicing predicted.3 Clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 0.545 based on 7 probands, falling in the neutral zone. Neither PP4 nor BP5 is applied.4 The variant was reported as a variant of unknown significance in 1 of 258 ovarian cancer patients by Smith et al. 2001 (PMID:11733976), identified in the RAD51-binding region of BRCA1. This observation alone does not meet any pathogenic criterion threshold.5 Overall classification: Likely Benign. Using the ENIGMA point system: BP1_Strong (-4) + BS1_Supporting (-1) = -5 points, which falls in the Likely Benign range (-6 to -2). No pathogenic criteria are met.
BRCA1
Final classification
Likely Benign
BRCA1 c.2998_3003del · p.Glu1000_Glu1001del
BRCA1
NM_007294.4:c.2998_3003del is an in-frame deletion of 6 nucleotides in BRCA1 exon 10 resulting in deletion of two glutamic acid residues at positions 1000-1001 (p.Glu1000_Glu1001del). This is not a null variant; PVS1 does not apply.
ENIGMA BRCA1 v1.2.0 Table 3 combination rules. Two benign criteria are met: BP1_Strong (in-frame deletion outside clinically important functional domains with no splicing predicted; SpliceAI max delta=0.01) and BS1_Supporting (FAF 0.0041% in gnomAD v4.1, within >0.002% and ≤0.01% range). No pathogenic criteria are met. 1 Strong (Benign) + 1 Supporting (Benign) satisfies ENIGMA Table 3 Likely Benign combination rule. ENIGMA point system: BP1_Strong (-4) + BS1_Supporting (-1) = -5, which falls in Likely Benign range (-6 to -2).
Classification rationale
BS1BP1
Likely Benign
BRCA1 c.2998_3003del
BS1 + BP1
→
Likely Benign
1
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
4
PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
ENIGMA BS1_Supporting applies when filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and ≤ 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 and/or v3.1/v4.1 non-cancer, non-founder populations. The maximum FAF is 4.101e-05 (0.0041%) in gnomAD v4.1, which falls within the BS1_Supporting range (>0.002%, ≤0.01%). The variant is observed in 5/282,204 alleles in v2.1 and 64/1,613,982 alleles in v4.1, with highest frequency in the European (non-Finnish) population (v4.1 NFE AF=0.00517%).
gnomAD v4.1 FAF = 4.101e-05 (0.0041%)within BS1_Supporting range (>0.002%≤0.01%)
✓
BP1
strong
Benign
ENIGMA BP1_Strong applies to in-frame deletions outside a clinically important functional domain with no splicing predicted (SpliceAI ≤ 0.1). The p.Glu1000_Glu1001del deletion is at positions 1000-1001, which is outside the three ENIGMA-defined clinically important functional domains: RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857). SpliceAI max delta score is 0.01, indicating no predicted splicing impact.
In-frame deletion at p.E1000_E1001deloutside RING (2-101)coiled-coil (1391-1424)
Assessed · not applied
Pathogenic
PVS1
NM_007294.4:c.2998_3003del is an in-frame 6-bp deletion resulting in p.(Glu1000_Glu1001del).
PS3
No variant-specific functional evidence demonstrating a damaging effect was identified.
PS4
ENIGMA PS4 requires case-control study with p≤0.05 and OR≥4 (lower CI excludes 2.0).
PM2
ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome only) and gnomAD v3.1/v4.1 (non-cancer).
PP1
No co-segregation data are available for this variant.
PP3
ENIGMA PP3 requires the variant to be a missense or in-frame insertion/deletion/delins variant inside a clinically important functional domain (RING aa 2-101, coiled-coil aa 1391-1424, or BRCT aa 1650-1857) with BayesDel no-AF score ≥0.28, OR SpliceAI ≥0.2 for splicing prediction.
PP4
ENIGMA PP4 is based on clinical-history likelihood ratio from Li et al.
Benign
BA1
ENIGMA BA1 (Stand Alone) requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or gnomAD v3.1/v4.1 (non-cancer).
BS2
ENIGMA BS2 requires observation in a homozygous state, in trans with a pathogenic variant, or in cis with a pathogenic variant in the absence of Fanconi anemia phenotype.
BS3
No variant-specific well-established functional studies demonstrating no damaging effect on protein function were identified.
BS4
No segregation data are available to assess lack of segregation.
BP4
ENIGMA BP4 requires the variant to be a missense or in-frame insertion/deletion/delins variant inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.15 and SpliceAI ≤ 0.1).
BP5
ENIGMA BP5 is based on clinical-history likelihood ratio from Li et al.
BP7
ENIGMA BP7_Strong (RNA) requires well-established in vitro/in vivo functional studies showing no damaging effect as measured by mRNA transcript profile.
N/A · 11
PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.96535e-05; MAF= 0.00397%, 64/1613982 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.16947e-05; MAF= 0.00517%, 61/1180004 alleles, homozygotes = 0); grpmax FAF= 4.101e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.77177e-05; MAF= 0.00177%, 5/282204 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.88066e-05; MAF= 0.00388%, 5/128844 alleles, homozygotes = 0); grpmax FAF= 1.124e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.004%
· 64 / 1,613,982
0 hom · FAF 0.0041%
0 hom · FAF 0.0041%
European (non-Finnish) 61 / 1,180,004 |
0.0052% |
African/African American 2 / 74,926 |
0.0027% |
Remaining individuals 1 / 62,488 |
0.0016% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0018%
· 5 / 282,204
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
European (non-Finnish) 5 / 128,844 |
0.0039% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 54743)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
27375968 ↗
Design and validation of a next generation sequencing assay for hereditary BRCA1 and BRCA2 mutation testing.
CLINVAR
10359546 ↗
Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.
CLINVAR
11733976 ↗
BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: a Gynecologic Oncology Group study.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR