Is BRCA1 p.Thr539Met (c.1616C>T) pathogenic?

BRCA1 p.Thr539Met (c.1616C>T) is classified Benign in BRCA1 (ClinVar, Expert panel, 19 submitters; last evaluated 2019-06-18). AlphaMissense: likely benign (0.0553); Ultra-rare (popmax 0.0496%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Thr539Met (c.1616C>T)?

BRCA1 p.Thr539Met (c.1616C>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.Thr539Met (c.1616C>T) in the general population?

BRCA1 p.Thr539Met (c.1616C>T) is ultra-rare (popmax 0.0496%, mid) (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.Thr539Met (c.1616C>T)?

AlphaMissense predicts likely benign (score 0.0553) — an in-silico prediction, not a clinical call.

BRCA1 p.Thr539Met

c.1616C>T · rs80357374 · VCV54310

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.0553 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.0553	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.011	GERP -5.4
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	1.226	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 0.0496% Middle Eastern · 3/6,052 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00502% 81/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,017
South Asian	0.0428%	2,335
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.00305%	32,776
African / African-American	0.00133%	75,008

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.Thr539Met
Coding: c.1616C>T
MANE Select: NM_007294
dbSNP: rs80357374
Type: single nucleotide variant
Location: chr17:43093915 (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 hereditary breast carcinoma Fanconi anemia, complementation group S

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Thr539= Likely 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-thr539met (accessed [today's date]).

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