Is BRCA2 p.Asp224del (c.670_672del) pathogenic?

BRCA2 p.Asp224del (c.670672del) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-07). Very rare (popmax 0.00111%, sas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Asp224del (c.670_672del)?

BRCA2 p.Asp224del (c.670_672del) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Asp224del (c.670_672del) in the general population?

BRCA2 p.Asp224del (c.670_672del) is very rare (popmax 0.00111%, sas) (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.Asp224del

c.670_672del · rs1060502447 · VCV409519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -0.44, phastCons 0.14
Overall
CADD	10.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,088 alleles

Overall 0.000188% 3/1,597,180 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,850
South Asiangrpmax	0.00111%	90,088
European (non-Finnish)	8.57e-05%	1,166,630

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp224del
Coding: c.670_672del
MANE Select: NM_000059
dbSNP: rs1060502447
Type: Deletion
Location: chr13:32329479 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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

Also linked: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Asp224Ala Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asp224Asn Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asp224Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asp224Val Uncertain significance ★ ⚠ same residue
BRCA2 p.Asp224= Likely benign ★ same residue
BRCA2 c.5217_5224del Pathogenic ★★★ same condition
BRCA2 c.68-?_316+?del Pathogenic ★★★ same condition
BRCA2 c.8312del 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-asp224del (accessed [today's date]).

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