Is BRCA2 p.Asn2553del (c.7658_7660del) pathogenic?

BRCA2 p.Asn2553del (c.76587660del) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-16). Very rare (popmax 0.000254%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Asn2553del (c.7658_7660del)?

BRCA2 p.Asn2553del (c.7658_7660del) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Asn2553del (c.7658_7660del) in the general population?

BRCA2 p.Asn2553del (c.7658_7660del) is very rare (popmax 0.000254%, 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.Asn2553del

c.7658_7660del · rs773148109 · VCV409478

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

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 0.44	GERP -4, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,792 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,484 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,246
European (non-Finnish)grpmax	0.000254%	393,264

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.Asn2553del
Coding: c.7658_7660del
MANE Select: NM_000059
dbSNP: rs773148109
Type: Deletion
Location: chr13:32357781 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2553: 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

Also linked: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Asn2553Asp Uncertain significance ★★ same residue
BRCA2 p.Asn2553Lys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Asn2553Ser Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Asn2553= Likely benign ★ same residue
BRCA2 p.Asn2553fs Likely pathogenic ★ 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-asn2553del (accessed [today's date]).

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