Is BRCA2 p.Ile2944Phe (c.8830A>T) pathogenic?

BRCA2 p.Ile2944Phe (c.8830A>T) is classified Benign in BRCA2 (ClinVar, Expert panel, 37 submitters; last evaluated 2015-01-12). AlphaMissense: likely benign (0.1426); Low-frequency (popmax 4.16%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ile2944Phe (c.8830A>T)?

BRCA2 p.Ile2944Phe (c.8830A>T) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 p.Ile2944Phe (c.8830A>T) in the general population?

BRCA2 p.Ile2944Phe (c.8830A>T) is low-frequency (popmax 4.16%, afr) (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.

What do computational predictors say about BRCA2 p.Ile2944Phe (c.8830A>T)?

AlphaMissense predicts likely benign (score 0.1426) — an in-silico prediction, not a clinical call.

BRCA2 p.Ile2944Phe

c.8830A>T · rs4987047 · VCV41569

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 37 submitters

AlphaMissense

likely benign

0.1426 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.16%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.1426	likely benign
REVEL	0.268	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP -0.49, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.16% African / African-American · 3,121/75,024 alleles

Filtering AF 4.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.99%

Overall 0.217% 3,501/1,613,882 alleles · low-frequency exomes 1,722/1,461,576 · genomes 1,779/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.16%	24
Remaining individualsnot grpmax-eligible	0.283%	353
Admixed American	0.247%	405
Middle Eastern	0.231%	433
South Asian	0.0121%	8,275
European (non-Finnish)	0.00254%	39,330

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.Ile2944Phe
Coding: c.8830A>T
MANE Select: NM_000059
dbSNP: rs4987047
Type: single nucleotide variant
Location: chr13:32379392 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2944: a UniProt-annotated variant site (in)

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

Disease context

breast-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome medulloblastoma prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma breast neoplasm BRCA2-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ile2944Met Uncertain significance ★★ ⚠ same residue
BRCA2 p.Ile2944= Likely benign ★ same residue
BRCA2 p.Ile2944fs Pathogenic ★★★ same residue
BRCA2 p.Ile2944delinsAspProValGlyAsnTer Pathogenic ★ same residue
BRCA2 p.Ile2944delinsGlyProGlyAlaValAlaHisAlaCysAsnProSerThrLeuGlyGlyArgGlyGlyArgIleThrArgSerGlyAspArgAspHisProGlyTer 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-ile2944phe (accessed [today's date]).

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