The BRCA1 c.101C>T (p.Pro34Leu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as Likely Pathogenic.1 This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (5/1,613,658 alleles; AF 3.10e-06; grpmax FAF 1.24e-06).2 In a calibrated BRCA1 functional study summarized by the ENIGMA BRCA1 specification, c.101C>T (p.Pro34Leu) showed loss of function/complete functional impact, supporting PS3_Strong.3 This missense change is located in the BRCA1 RING domain; BayesDel is 0.450189, above the ENIGMA PP3 threshold of 0.28, REVEL is 0.837, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a damaging protein effect without predicted splice disruption.4
Final classification
Likely pathogenic
PS3PP3PP5
BRCA1
c.101C>T
p.Pro34Leu
This variant
The BRCA1 c.101C>T (p.Pro34Leu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as Likely Pathogenic.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 final-classification framework
Classification rationale
PS3PP3PP5
Likely pathogenic
BRCA1 c.101C>T
PS3 + PP3 + PP5
→
Likely pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18PMID:30209399 ↗
4
cspec ↗bayesdelrevelspliceai ↗vcep_appendices_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 · 3 applied · 14 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In the ENIGMA BRCA1 functional evidence table, this exact variant is assigned PS3_Strong based on a calibrated functional study. The cited study reported loss-of-function/complete functional impact for c.101C>T (p.Pro34Leu), supporting a damaging effect on BRCA1 function.
ENIGMA Table 9 lists BRCA1 c.101C>T p.(Pro34Leu) as PS3 Strong.Table 9 cites Findlay 2018 as the supporting calibrated study.
PP3
supporting
Pathogenic
This missense variant lies in the BRCA1 RING domain, a clinically important functional domain, and BayesDel is 0.450189, which is above the ENIGMA PP3 threshold of 0.28. REVEL is also high at 0.837, while SpliceAI predicts no significant splice impact (max delta score 0.01), supporting a damaging protein effect rather than a splice-driven mechanism.
BRCA1 RING domain spans amino acids 2-101.BayesDel score 0.450189.REVEL score 0.837.
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PS1
No validated evidence was identified showing that this variant produces the same amino acid or splice consequence as a different previously established pathogenic BRCA1 variant, so PS1 was not assessed.
PS4
No case-control study, odds ratio, or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 5/1,613,658 alleles (AF 3.10e-06; grpmax FAF 1.24e-06).
PM3
No evidence was identified for co-occurrence with another BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed.
PP1
No segregation data were identified for this variant, and no quantitative co-segregation likelihood ratio was available, so PP1 was not assessed.
PP4
No variant-level personal or family history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed.
Benign
BA1
The highest available population filter allele frequency is far below the ENIGMA BA1 threshold of greater than 0.1%.
BS1
The available population frequency is below ENIGMA BS1 thresholds.
BS2
No data were identified showing the variant in individuals without features of BRCA1-related Fanconi anemia at a level that would satisfy the ENIGMA point-based BS2 framework, so BS2 was not assessed.
BS3
Available functional evidence does not show a benign or neutral effect.
BS4
No lack-of-segregation data or quantitative segregation likelihood ratio against pathogenicity was identified for this variant, so BS4 was not assessed.
BP1
This missense variant is located in the BRCA1 RING domain (amino acids 2-101), which is a clinically important functional domain.
BP4
This variant does not meet the ENIGMA BP4 rule because BayesDel is 0.450189, which is above the benign threshold of 0.15, although SpliceAI predicts no significant splice impact (max delta score 0.01).
BP5
No variant-level multifactorial clinical likelihood ratio against pathogenicity was identified for this variant, so BP5 was not assessed.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09855e-06; MAF= 0.00031%, 5/1613658 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23801e-06; MAF= 0.00042%, 5/1179798 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,613,658
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,179,798 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic 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 = 0.01). REVEL score = 0.837. BayesDel score = 0.450189.
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
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Accurate classification of BRCA1 variants with saturation genome editing.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links