Is BRCA2 p.Arg2502His (c.7505G>A) pathogenic?

BRCA2 p.Arg2502His (c.7505G>A) is classified Benign in BRCA2 (ClinVar, Expert panel, 20 submitters; last evaluated 2019-06-18). AlphaMissense: likely benign (0.0669); Ultra-rare (popmax 0.0263%, sas); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Arg2502His (c.7505G>A)?

BRCA2 p.Arg2502His (c.7505G>A) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Arg2502His (c.7505G>A) in the general population?

BRCA2 p.Arg2502His (c.7505G>A) is ultra-rare (popmax 0.0263%, 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.

What do computational predictors say about BRCA2 p.Arg2502His (c.7505G>A)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2502His

c.7505G>A · rs56070345 · VCV52345

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.282	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -4.6
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	0.619	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 0.0263% South Asian · 24/91,084 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00446% 72/1,614,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,795
East Asian	0.00446%	22,443
European (non-Finnish)	0.00364%	27,442
Remaining individualsnot grpmax-eligible	0.0032%	31,253
African / African-American	0.00133%	75,056

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.Arg2502His
Coding: c.7505G>A
MANE Select: NM_000059
dbSNP: rs56070345
Type: single nucleotide variant
Location: chr13:32356497 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2502: a UniProt-annotated variant site (in bc; uncertain significance); a UniProt-annotated variant site (in); the 'interaction with fancd2' region; 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 hereditary neoplastic syndrome BRCA2-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Arg2502Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2502Leu Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2502Pro Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2502Ser Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2502= Likely benign ★ same residue
BRCA2 p.Arg2502fs Pathogenic ★★★ same residue
BRCA2 p.Arg2502Gly Uncertain significance ★ same residue
BRCA2 c.316+1G>T 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-arg2502his (accessed [today's date]).

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