Is BRCA2 p.Asn1666fs (c.4997del) pathogenic?

BRCA2 p.Asn1666fs (c.4997del) is classified Likely pathogenic in BRCA2 (ClinVar, No assertion criteria, 1 submitter). Absent from gnomAD; Associated with polyposis syndrome, hereditary mixed, 1.

What condition is associated with BRCA2 p.Asn1666fs (c.4997del)?

BRCA2 p.Asn1666fs (c.4997del) is associated with polyposis syndrome, hereditary mixed, 1 (ClinVar).

How common is BRCA2 p.Asn1666fs (c.4997del) in the general population?

BRCA2 p.Asn1666fs (c.4997del) is absent from gnomAD (gnomAD).

How is Hereditary mixed polyposis syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

BRCA2 p.Asn1666fs

c.4997del · rs2548529774 · VCV1703201

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

polyposis syndrome, hereditary mixed, 1

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 11 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP -0.61, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BRCA2
Protein: p.Asn1666fs
Coding: c.4997del
MANE Select: NM_000059
dbSNP: rs2548529774
Type: Deletion
Location: chr13:32339349 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1666: the 'interaction with rad51' region; the 'interaction with polh' region

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

Disease context

polyposis syndrome, hereditary mixed, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary mixed polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

BRCA2 p.Lys838fs Pathogenic ★★★ same condition
BRCA2 p.Asn1666Asp Uncertain significance ★ ⚠ same residue
BRCA2 p.Asn1666Ser Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Lys3327fs Uncertain significance ★ same condition
BRCA2 p.Asn1147fs Likely pathogenic same condition
BRCA2 p.Asn1312fs Likely pathogenic same condition
BRCA2 p.Ile1490fs Likely pathogenic same condition
BRCA2 p.Lys3267fs Likely 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-asn1666fs (accessed [today's date]).

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