Is BRCA2 p.Arg2669= (c.8007A>G) pathogenic?

BRCA2 p.Arg2669= (c.8007A>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0987%, mid); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Arg2669= (c.8007A>G)?

BRCA2 p.Arg2669= (c.8007A>G) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Arg2669= (c.8007A>G) in the general population?

BRCA2 p.Arg2669= (c.8007A>G) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

BRCA2 p.Arg2669=

c.8007A>G · rs143999963 · VCV188439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -0.22, phastCons 1
Overall
CADD	7.221	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0987% Middle Eastern · 6/6,082 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.000806% 13/1,613,772 alleles · ultra-rare exomes 10/1,461,556 · genomes 3/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,014
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000424%	235,988

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.Arg2669=
Coding: c.8007A>G
MANE Select: NM_000059
dbSNP: rs143999963
Type: single nucleotide variant
Location: chr13:32363209 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2669: the 'interaction with sem1' region

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

Disease context

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

Similar variants

BRCA2 p.Arg2669Gly Uncertain significance ★ ⚠ same residue
BRCA2 p.Arg2669Ile Uncertain significance ★ ⚠ same residue
BRCA2 p.Arg2669Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2669del Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2669Ter 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

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-arg2669 (accessed [today's date]).

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