Is BRCA1 p.Lys894fs (c.2681_2682del) pathogenic?

BRCA1 p.Lys894fs (c.26812682del) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 30 submitters; last evaluated 2016-04-22). Very rare (popmax 0.00186%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Lys894fs (c.2681_2682del)?

BRCA1 p.Lys894fs (c.2681_2682del) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Lys894fs (c.2681_2682del) in the general population?

BRCA1 p.Lys894fs (c.2681_2682del) is very rare (popmax 0.00186%, nfe) (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.Lys894fs

c.2681_2682del · rs80357971 · VCV17667

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 30 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

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	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 10 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP 0.03, phastCons 0.78
Overall
CADD	22.7	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 0.00186% European (non-Finnish) · 22/1,179,954 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 22/1,613,724 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.Lys894fs
Coding: c.2681_2682del
MANE Select: NM_007294
dbSNP: rs80357971
Type: Deletion
Location: chr17:43092849 (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

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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Lys894Ter Pathogenic ★★★ same residue
BRCA1 p.Lys894= Likely benign ★★★ same residue
BRCA1 p.Lys894Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Lys894Gln Uncertain significance ★ ⚠ same residue
BRCA1 p.Lys894Ile Uncertain significance ★ ⚠ same residue
BRCA1 c.302-2del Pathogenic ★★★ same condition
BRCA1 c.4358_4484del Pathogenic ★★★ same condition
BRCA1 c.442-22_442-13del 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-lys894fs (accessed [today's date]).

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