Is BRCA2 p.Gly2528fs (c.7582_7583insA) pathogenic?

BRCA2 p.Gly2528fs (c.75827583insA) is classified Likely pathogenic in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-14). Very rare (popmax 0.000508%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Gly2528fs (c.7582_7583insA)?

BRCA2 p.Gly2528fs (c.7582_7583insA) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Gly2528fs (c.7582_7583insA) in the general population?

BRCA2 p.Gly2528fs (c.7582_7583insA) is very rare (popmax 0.000508%, 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.

BRCA2 p.Gly2528fs

c.7582_7583insA · rs2548541644 · VCV3075790

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 15 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 1.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,030 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,884 alleles · very rare

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.Gly2528fs
Coding: c.7582_7583insA
MANE Select: NM_000059
dbSNP: rs2548541644
Type: Insertion
Location: chr13:32356574 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2528: the 'interaction with fancd2' region; the 'interaction with sem1' region

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

Disease context

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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Gly2528Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 c.156_157insAlu Pathogenic ★★★ same condition
BRCA2 p.Ala1825fs Pathogenic ★★★ same condition
BRCA2 p.Ala2534fs Pathogenic ★★★ same condition
BRCA2 p.Asn1747fs Pathogenic ★★★ same condition
BRCA2 p.Asn2460fs Pathogenic ★★★ same condition
BRCA2 p.Asp1337fs Pathogenic ★★★ same condition
BRCA2 p.Cys1365fs 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-gly2528fs (accessed [today's date]).

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