Is BRCA2 p.Arg2784Trp (c.8350C>T) pathogenic?

BRCA2 p.Arg2784Trp (c.8350C>T) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 31 submitters; last evaluated 2026-08-04). AlphaMissense: ambiguous (0.5032); Ultra-rare (popmax 0.0165%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Arg2784Trp (c.8350C>T)?

BRCA2 p.Arg2784Trp (c.8350C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 p.Arg2784Trp (c.8350C>T) in the general population?

BRCA2 p.Arg2784Trp (c.8350C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg2784Trp (c.8350C>T)?

AlphaMissense predicts ambiguous (score 0.5032) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2784Trp

c.8350C>T · rs80359075 · VCV38155

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 31 submitters

AlphaMissense

ambiguous

0.5032 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.5032	ambiguous · top 8% in BRCA2
REVEL	0.738	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.19, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000496% 8/1,613,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
East Asian	0.00223%	44,880
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,502
African / African-American	0.00133%	75,012
South Asian	0.0011%	91,072
European (non-Finnish)	0.00017%	589,828

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.Arg2784Trp
Coding: c.8350C>T
MANE Select: NM_000059
dbSNP: rs80359075
Type: single nucleotide variant
Location: chr13:32370420 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2784: the 'interaction with sem1' region

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 Wilms tumor 1 chordoma Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma BRCA2-related cancer predisposition prostate cancer, hereditary

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Arg2784= Likely benign ★★★ same residue
BRCA2 p.Arg2784Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2784Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2784fs 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
BRCA2 c.316+5G>C 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-arg2784trp (accessed [today's date]).

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