Is BRCA1 p.Thr1561Ile (c.4682C>T) pathogenic?

BRCA1 p.Thr1561Ile (c.4682C>T) is classified Benign/Likely benign in BRCA1 (ClinVar, Multiple submitters, 26 submitters; last evaluated 2026-09-04). AlphaMissense: likely benign (0.1583); Rare (popmax 0.425%, afr); Associated with hereditary breast carcinoma.

What condition is associated with BRCA1 p.Thr1561Ile (c.4682C>T)?

BRCA1 p.Thr1561Ile (c.4682C>T) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 p.Thr1561Ile (c.4682C>T) in the general population?

BRCA1 p.Thr1561Ile (c.4682C>T) is rare (popmax 0.425%, afr) (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about BRCA1 p.Thr1561Ile (c.4682C>T)?

AlphaMissense predicts likely benign (score 0.1583) — an in-silico prediction, not a clinical call.

BRCA1 p.Thr1561Ile

c.4682C>T · rs56158747 · VCV55259

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 26 submitters

AlphaMissense

likely benign

0.1583 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.425%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1583	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -6.63	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -4.4
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	17.45	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 0.425% African / African-American · 319/75,034 alleles

Filtering AF 0.387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.0233% 376/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.425%	235
Admixed American	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.032%	3,126
South Asian	0.00329%	30,363
European (non-Finnish)	8.47e-05%	1,179,967

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.Thr1561Ile
Coding: c.4682C>T
MANE Select: NM_007294
dbSNP: rs56158747
Type: single nucleotide variant
Location: chr17:43071232 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1561: a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (found in breast cancer; uncertain significance)

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

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast cancer breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome breast neoplasm Fanconi anemia, complementation group S BRCA1-related cancer predisposition

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRCA1 p.Thr1561= Likely benign ★★★ same residue
BRCA1 p.Thr1561Asn Uncertain significance ★★ ⚠ same residue
BRCA1 p.Thr1561fs 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
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G 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-thr1561ile (accessed [today's date]).

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