Is BRCA2 p.Phe1524Val (c.4570T>G) pathogenic?

BRCA2 p.Phe1524Val (c.4570T>G) is classified Benign in BRCA2 (ClinVar, Expert panel, 20 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.7939); Very rare (popmax 0.00356%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Phe1524Val (c.4570T>G)?

BRCA2 p.Phe1524Val (c.4570T>G) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Phe1524Val (c.4570T>G) in the general population?

BRCA2 p.Phe1524Val (c.4570T>G) is very rare (popmax 0.00356%, nfe) (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 BRCA2 p.Phe1524Val (c.4570T>G)?

AlphaMissense predicts likely pathogenic (score 0.7939) — an in-silico prediction, not a clinical call.

BRCA2 p.Phe1524Val

c.4570T>G · rs56386506 · VCV51676

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.7939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.7939	likely pathogenic · top 4% in BRCA2
REVEL	0.913	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,179,898 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0026% 42/1,613,784 alleles · very rare exomes 37/1,461,644 · genomes 5/152,140 · joint denominator

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: BRCA2
Protein: p.Phe1524Val
Coding: c.4570T>G
MANE Select: NM_000059
dbSNP: rs56386506
Type: single nucleotide variant
Location: chr13:32338925 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1524: the 'interaction with rad51' region; the 'interaction with polh' region; the 'required for stimulation of polh dna polymerization activity' region; a UniProt-annotated variant site (in bc; benign)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast-ovarian cancer, familial, susceptibility to, 2 — 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

BRCA2 p.Phe1524Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Phe1524Leu Uncertain significance ★ ⚠ same residue
BRCA2 p.Phe1524= Likely benign ★ same residue
BRCA2 p.Phe1524fs Pathogenic/Likely pathogenic ★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C 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/brca2-p-phe1524val (accessed [today's date]).

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