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
BRCA1
Final classification
Likely pathogenic
BRCA1 c.101C>T · p.Pro34Leu
BRCA1
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
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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 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.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links