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
Final classification
Likely Benign
BP1BP6
BRCA1
c.4159T>C
p.Ser1387Pro
This variant
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
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 · 2 applied · 15 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
BP1
strong
Benign
p.(Ser1387Pro) is a missense variant outside the ENIGMA BRCA1 clinically important domains, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the BP1_Strong threshold of 0.1. This meets ENIGMA BRCA1 BP1_Strong.
Residue 1387 is outside RING aa 2-101coiled-coil aa 1391-1424and BRCT aa 1650-1857
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PS1
No evidence was identified showing that this variant produces the same protein change as a previously established pathogenic or likely pathogenic BRCA1 variant, and no matched splice mechanism was identified.
PS3
No calibrated variant-specific functional study supporting a damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so PS3 was not applied.
PS4
Available evidence does not show a case-control enrichment study or other quantitative affected-versus-control analysis meeting ENIGMA BRCA1 PS4 requirements for this variant.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified showing this variant in the biallelic Fanconi anemia context required for ENIGMA BRCA1 PM3 scoring.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not applied.
PP3
ENIGMA BRCA1 PP3 for missense variants requires location in a clinically important functional domain with BayesDel no-AF score at least 0.28, or predicted splice impact with SpliceAI at least 0.2.
PP4
The BRCA1 clinical-history likelihood ratio for this variant is 0.645 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08 and falls in the neutral zone, so PP4 is not met.
Benign
BA1
The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is far below the ENIGMA BRCA1 BA1 threshold of 0.001, so BA1 is not met.
BS1
The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is below the ENIGMA BRCA1 BS1 thresholds of greater than 0.00002 for BS1_Supporting and greater than 0.0001 for BS1, so BS1 is not met.
BS2
No evidence was identified showing this variant in the unaffected or non-Fanconi-anemia context required for ENIGMA BRCA1 BS2 point assignment.
BS3
No calibrated variant-specific functional study showing no damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so BS3 was not applied.
BS4
No quantitative lack-of-segregation data were identified for this variant, so BS4 was not applied.
BP5
The BRCA1 clinical-history likelihood ratio for this variant is 0.645 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met.
BP7
No RNA study showing a normal transcript profile was identified for this variant, so BP7 was not applied.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4
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.
Sources & reference links