Is BRCA2 p.Arg2287fs (c.6859_6863del) pathogenic?

BRCA2 p.Arg2287fs (c.68596863del) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-08). Very rare (popmax 8.9e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg2287fs (c.6859_6863del)?

BRCA2 p.Arg2287fs (c.6859_6863del) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Arg2287fs (c.6859_6863del) in the general population?

BRCA2 p.Arg2287fs (c.6859_6863del) is very rare (popmax 8.9e-05%, nfe) (gnomAD).

BRCA2 p.Arg2287fs

c.6859_6863del · rs398122568 · VCV91461

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.9e-05%, nfe)

Conditions

hereditary neoplastic 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 12 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.51	GERP -1.6, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.9e-05% European (non-Finnish) · 1/1,123,388 alleles

Overall 7.16e-05% 1/1,395,992 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.Arg2287fs
Coding: c.6859_6863del
MANE Select: NM_000059
dbSNP: rs398122568
Type: Deletion
Location: chr13:32344572 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2287: the 'interaction with hsf2bp' region

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

Disease context

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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2

Similar variants

BRCA2 p.Arg2287Ter Pathogenic ★★★ same residue
BRCA2 p.Arg2287Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg2287= Likely benign ★★ same residue
BRCA2 p.Arg2287Ile Uncertain significance ★ ⚠ same residue
BRCA2 p.Arg2287Ser Uncertain significance ★ same residue
BRCA2 c.316+4del Pathogenic ★★★ same condition
BRCA2 c.5217_5224del Pathogenic ★★★ same condition
BRCA2 c.68-?_316+?del 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-arg2287fs (accessed [today's date]).

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