Is BRCA2 p.Arg118His (c.353G>A) pathogenic?

BRCA2 p.Arg118His (c.353G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.0707); Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Arg118His (c.353G>A)?

BRCA2 p.Arg118His (c.353G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, malignant pancreatic neoplasm (ClinVar).

How common is BRCA2 p.Arg118His (c.353G>A) in the general population?

BRCA2 p.Arg118His (c.353G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Arg118His (c.353G>A)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg118His

c.353G>A · rs80358603 · VCV37845

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.334	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -4.2
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	0.538	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 0.0107% African / African-American · 8/74,748 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00218% 35/1,607,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,344
Remaining individualsnot grpmax-eligible	0.00321%	31,128
Finnishnot grpmax-eligible	0.00313%	31,911
European (non-Finnish)	0.00187%	53,385
South Asian	0.0011%	90,948

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.Arg118His
Coding: c.353G>A
MANE Select: NM_000059
dbSNP: rs80358603
Type: single nucleotide variant
Location: chr13:32325112 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 118: a UniProt-annotated variant site (in one patient with esophageal carcinoma)

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

Disease context

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

Also linked: hereditary breast ovarian cancer syndrome malignant pancreatic neoplasm breast-ovarian cancer, familial, susceptibility to, 2 hereditary breast carcinoma prostate cancer, hereditary

Similar variants

BRCA2 p.Arg118Leu Uncertain significance ★★ same residue
BRCA2 p.Arg118Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg118Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg118Pro Uncertain significance ★ same residue
BRCA2 p.Arg118= Likely benign ★ same residue
BRCA2 p.Arg118fs Pathogenic ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>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-arg118his (accessed [today's date]).

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