Is BRCA1 p.Pro34Leu (c.101C>T) pathogenic?

BRCA1 p.Pro34Leu (c.101C>T) is classified Likely pathogenic in BRCA1 (ClinVar, Expert panel, 5 submitters; last evaluated 2026-01-04). AlphaMissense: likely pathogenic (0.9811); Very rare (popmax 0.000424%, nfe); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Pro34Leu (c.101C>T)?

BRCA1 p.Pro34Leu (c.101C>T) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Pro34Leu (c.101C>T) in the general population?

BRCA1 p.Pro34Leu (c.101C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Pro34Leu (c.101C>T)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

BRCA1 p.Pro34Leu

c.101C>T · rs786203319 · VCV186913

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Likely Pathogenic for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PP4_Moderate PS3 PP3

Curation rationale (ClinGen, verbatim)

The c.101C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA1 missense variant is within a key functional domain and a SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1). The computational predictor BayesDel (noAF) gives a score of 0.45, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930, 37168384) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 5.47 (based on Case-Control LR=5.47), within the thresholds for moderate evidence towards pathogenicity (LR ≥4.3 & <18.7) (PP4_Moderate met; PMID: 40413188). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PP4_Moderate).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,798 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,432 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BRCA1
Protein: p.Pro34Leu
Coding: c.101C>T
MANE Select: NM_007294
dbSNP: rs786203319
Type: single nucleotide variant
Location: chr17:43115759 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

Similar variants

BRCA1 p.Pro34Ser Likely pathogenic ★★★ same residue
BRCA1 p.Pro34Arg Likely pathogenic ★ same residue
BRCA1 p.Pro34Thr Uncertain significance ★ ⚠ same residue
BRCA1 p.Pro34= Likely benign ★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition
BRCA1 c.212+1G>T Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/brca1-p-pro34leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown