Is BRCA1 p.Glu1559Lys (c.4675G>A) pathogenic?

BRCA1 p.Glu1559Lys (c.4675G>A) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 18 submitters; last evaluated 2019-06-18). AlphaMissense: likely benign (0.1339); Very rare (popmax 8.48e-05%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Glu1559Lys (c.4675G>A)?

BRCA1 p.Glu1559Lys (c.4675G>A) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Glu1559Lys (c.4675G>A) in the general population?

BRCA1 p.Glu1559Lys (c.4675G>A) is very rare (popmax 8.48e-05%, 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.

What do computational predictors say about BRCA1 p.Glu1559Lys (c.4675G>A)?

AlphaMissense predicts likely benign (score 0.1339) — an in-silico prediction, not a clinical call.

BRCA1 p.Glu1559Lys

c.4675G>A · rs80356988 · VCV37604

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1339 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1339	likely benign ⚠ discordant with ClinVar
REVEL	0.765	pathogenic-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.77	donor loss at this position · raw score · deltas
Pangolin	Δ0.78	loss · gain 0.72 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	35.0	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 8.48e-05% European (non-Finnish) · 1/1,179,808 alleles

Overall 0.000124% 2/1,613,716 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,026
European (non-Finnish)grpmax	8.48e-05%	1,179,807

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu1559Lys
Coding: c.4675G>A
MANE Select: NM_007294
dbSNP: rs80356988
Type: single nucleotide variant
Location: chr17:43074331 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1559: a UniProt-annotated variant site (in fancs)

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.Glu1559Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
BRCA1 p.Glu1559Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Glu1559Ter Pathogenic ★ same residue
BRCA1 p.Glu1559Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Glu1559= Likely benign ★ same residue
BRCA1 p.Glu1559fs Pathogenic ★★★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>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-glu1559lys (accessed [today's date]).

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