The BRCA1 c.4159T>C (p.Ser1387Pro) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as Likely Benign despite conflicting individual submissions.1 This variant is present at very low frequency in population databases, including gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%; grpmax FAF 2.8e-07), which is too low for BA1 or BS1 and means PM2 is not met because the variant is not absent from controls.2 No exact curated functional assay result for p.(Ser1387Pro) was identified in the ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied from the available functional evidence.3 In silico data support a benign interpretation under the ENIGMA BRCA1 framework because p.(Ser1387Pro) lies outside the BRCA1 clinically important domains, SpliceAI predicts no splice impact (max delta 0.00), and the missense change therefore meets BP1_Strong; BayesDel is 0.148379 and PP3 is not met.4
BRCA1
Final classification
Likely Benign
BRCA1 c.4159T>C · p.Ser1387Pro
BRCA1
The BRCA1 c.4159T>C (p.Ser1387Pro) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as Likely Benign despite conflicting individual submissions.
Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework using Table 3 adapted ACMG/AMP combination rules.
Classification rationale
BP1BP6
Likely Benign
BRCA1 c.4159T>C
BP1 + BP6
→
Likely Benign
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
4
cspec ↗spliceai ↗bayesdel
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24043e-06; MAF= 0.00012%, 2/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69594e-06; MAF= 0.00017%, 2/1179284 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.02755e-06; MAF= 0.00040%, 1/248290 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89696e-06; MAF= 0.00089%, 1/112398 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,612,348
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,179,284 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 248,290
0 hom
0 hom
European (non-Finnish) 1 / 112,398 |
0.00089% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Likely Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.481. BayesDel score = 0.148379.
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.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID cspec
Found
Structured finding pending for this record — see source link.
Applied to
→BP1 supports · met
→BP6 supports · met
PMID vcep_appendices_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→BP1 supports · met
Sources & reference links