Is BRCA1 p.Gln12Ter (c.34C>T) pathogenic?

BRCA1 p.Gln12Ter (c.34C>T) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 22 submitters; last evaluated 2016-04-22). Very rare (popmax 0.00223%, eas); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Gln12Ter (c.34C>T)?

BRCA1 p.Gln12Ter (c.34C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Gln12Ter (c.34C>T) in the general population?

BRCA1 p.Gln12Ter (c.34C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

BRCA1 p.Gln12Ter

c.34C>T · rs80357134 · VCV54902

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 22 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 23
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.40	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.2	phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,838 alleles

Overall 0.000186% 3/1,613,790 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,838
South Asian	0.0011%	91,080
European (non-Finnish)	8.48e-05%	1,179,800

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.Gln12Ter
Coding: c.34C>T
MANE Select: NM_007294
dbSNP: rs80357134
Type: single nucleotide variant
Location: chr17:43124063 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 12: an α-helix

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

Disease context

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome ovarian neoplasm BRCA1-related cancer predisposition

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Gln12= Likely benign ★★★ same residue
BRCA1 p.Gln12Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Gln12Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Gln12Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Gln12Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Gln12Leu Likely benign ★ ⚠ same residue
BRCA1 p.Gln12fs Pathogenic ★★★ same residue
BRCA1 c.134+3A>T Likely 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-gln12ter (accessed [today's date]).

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