Is BRCA1 p.Phe486Leu (c.1456T>C) pathogenic?

BRCA1 p.Phe486Leu (c.1456T>C) is classified Benign in BRCA1 (ClinVar, Expert panel, 39 submitters; last evaluated 2015-08-10). AlphaMissense: ambiguous (0.3568); Low-frequency (popmax 1.86%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Phe486Leu (c.1456T>C)?

BRCA1 p.Phe486Leu (c.1456T>C) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Phe486Leu (c.1456T>C) in the general population?

BRCA1 p.Phe486Leu (c.1456T>C) is low-frequency (popmax 1.86%, 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.Phe486Leu (c.1456T>C)?

AlphaMissense predicts ambiguous (score 0.3568) — an in-silico prediction, not a clinical call.

BRCA1 p.Phe486Leu

c.1456T>C · rs55906931 · VCV54258

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 39 submitters

AlphaMissense

ambiguous

0.3568 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.86%, mid)

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.3568	ambiguous
REVEL	0.567	indeterminate
SaProt	LLR -4.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -4.7
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	0.019	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 1.86% Middle Eastern · 113/6,062 alleles

Filtering AF 1.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.0348% 562/1,614,110 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.86%	54
Remaining individualsnot grpmax-eligible	0.0768%	1,302
Admixed American	0.0417%	2,401
South Asian	0.0351%	2,846
European (non-Finnish)	0.0274%	3,653
African / African-American	0.0253%	3,950
East Asian	0.00223%	44,866
Finnishnot grpmax-eligible	0.00156%	64,018

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.Phe486Leu
Coding: c.1456T>C
MANE Select: NM_007294
dbSNP: rs55906931
Type: single nucleotide variant
Location: chr17:43094075 (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 BRCA1-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Phe486Cys Uncertain significance ★ ⚠ same residue
BRCA1 p.Phe486Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Phe486Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Phe486= Likely benign ★ same residue
BRCA1 p.Phe486fs 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-phe486leu (accessed [today's date]).

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