Is BRCA1 p.Thr539= (c.1617G>A) pathogenic?

BRCA1 p.Thr539= (c.1617G>A) is classified Likely benign in BRCA1 (ClinVar, Expert panel, 19 submitters; last evaluated 2017-06-29). Very rare (popmax 0.00534%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Thr539= (c.1617G>A)?

BRCA1 p.Thr539= (c.1617G>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.Thr539= (c.1617G>A) in the general population?

BRCA1 p.Thr539= (c.1617G>A) is very rare (popmax 0.00534%, afr) (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.Thr539=

c.1617G>A · rs372002119 · VCV185046

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -4.1
Overall
CADD	5.844	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,876 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00211% 34/1,613,714 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,719
Admixed American	0.005%	19,989
South Asian	0.00329%	30,351
European (non-Finnish)	0.00195%	51,302
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Thr539=
Coding: c.1617G>A
MANE Select: NM_007294
dbSNP: rs372002119
Type: single nucleotide variant
Location: chr17:43093914 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 539: the 'disordered' region

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.Thr539Met Benign ★★★ ⚠ same residue
BRCA1 p.Thr539Ala Uncertain significance ★ ⚠ same residue
BRCA1 p.Thr539Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Thr539Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Thr539fs Pathogenic ★★★ 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

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-thr539 (accessed [today's date]).

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