Is BRCA1 p.Leu52Phe (c.154C>T) pathogenic?

BRCA1 p.Leu52Phe (c.154C>T) is classified Benign in BRCA1 (ClinVar, Expert panel, 22 submitters; last evaluated 2026-07-15). AlphaMissense: likely pathogenic (0.6023); Rare (popmax 0.23%, eas); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Leu52Phe (c.154C>T)?

BRCA1 p.Leu52Phe (c.154C>T) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, ovarian cancer (ClinVar).

How common is BRCA1 p.Leu52Phe (c.154C>T) in the general population?

BRCA1 p.Leu52Phe (c.154C>T) is rare (popmax 0.23%, eas) (gnomAD).

What do computational predictors say about BRCA1 p.Leu52Phe (c.154C>T)?

AlphaMissense predicts likely pathogenic (score 0.6023) — an in-silico prediction, not a clinical call.

BRCA1 p.Leu52Phe

c.154C>T · rs80357084 · VCV37421

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 22 submitters

AlphaMissense

likely pathogenic

0.6023 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.23%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Benign for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The c.154C>T variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 52 (p.(Leu52Phe)). The Total GrpMax filtering allele frequency (the lower threshold of the 95% CI) in gnomAD v4.1 is 0.001942 in the East Asian genetic ancestry group (based on 103/44742 alleles) which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (v1.2) (BA1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.6023	likely pathogenic · top 7% in BRCA1
REVEL	0.683	pathogenic-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.9	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 0.23% East Asian · 103/44,742 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.0065% 104/1,600,984 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.23%	434
European (non-Finnish)	8.55e-05%	1,169,194

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.Leu52Phe
Coding: c.154C>T
MANE Select: NM_007294
dbSNP: rs80357084
Type: single nucleotide variant
Location: chr17:43106514 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 52: an α-helix

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome ovarian cancer breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome

Similar variants

BRCA1 p.Leu52Pro Uncertain significance ★★ ⚠ same residue
BRCA1 p.Leu52Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Leu52Val Uncertain significance ★ ⚠ same residue
BRCA1 p.Leu52= Likely benign ★ 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

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-leu52phe (accessed [today's date]).

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