The BRCA1 c.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the available documentation was insufficient to assign BRCA1 ENIGMA PM2_Supporting under the full dataset and coverage requirements.2 Under the ENIGMA BRCA1 specification, this frameshift lies in exon 9(10), an exon designated PVS1_N/A and PM5_N/A for protein-truncating variants because rescue of an in-frame transcript is expected, so truncating status alone does not support PVS1 or PM5.3 SpliceAI shows a maximum delta score of 0.11, which is below the BRCA1 splice PP3 threshold of 0.20 and above the BP4 no-impact threshold of 0.10; however, the BRCA1 computational rules are not designed to add PP3 or BP4 evidence for this frameshift variant.4
Final classification
Uncertain Significance
BRCA1
c.615_622dup
p.Thr208AsnfsTer29
This variant
The BRCA1 c.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (ACMG/AMP 2015 with ENIGMA Table 3 adaptations)
Classification rationale
Uncertain Significance
BRCA1 c.615_622dup
3
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
· 2 not met · 8 not assessed
Pathogenic
PS4
This variant has been reported in ClinVar, but no case-control data were identified showing a significant enrichment in affected individuals with p-value 0.05 or less and odds ratio 4 or greater.
PM2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity.
PM3
PM3 in the BRCA1 ENIGMA specification is reserved for BRCA1- or BRCA2-related Fanconi anemia with qualifying trans observations and point-based evidence.
PP1
No quantitative co-segregation data were identified for this variant.
PP4
No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BRCA1 ENIGMA BA1 frequency threshold.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BRCA1 ENIGMA BS1 frequency thresholds.
BS2
BS2 in the BRCA1 ENIGMA framework requires point-based evidence from individuals without features of recessive disease, specifically Fanconi anemia.
BS4
No quantitative lack-of-segregation evidence was identified for this variant.
BP5
No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials.
N/A · 18
PVS1 · PS1 · PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BS3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 926510)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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
Triaged references · 9 PMIDs not cited in assessment
12947386 ↗
Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
ONCOKB
20608970 ↗
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
ONCOKB
12203997 ↗
Analysis of breast cancer susceptibility genes BRCA1 and BRCA2 in Thai familial and isolated early-onset breast and ovarian cancer.
CLINVAR
16211554 ↗
Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.
CLINVAR
19892845 ↗
Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study.
CLINVAR
20104584 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR