Is BRCA2 p.Cys3198Arg (c.9592T>C) pathogenic?

BRCA2 p.Cys3198Arg (c.9592T>C) is classified Benign in BRCA2 (ClinVar, Expert panel, 19 submitters; last evaluated 2015-08-10). AlphaMissense: likely benign (0.0842); Ultra-rare (popmax 0.0148%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Cys3198Arg (c.9592T>C)?

BRCA2 p.Cys3198Arg (c.9592T>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D1 (ClinVar).

How common is BRCA2 p.Cys3198Arg (c.9592T>C) in the general population?

BRCA2 p.Cys3198Arg (c.9592T>C) is ultra-rare (popmax 0.0148%, nfe) (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.Cys3198Arg (c.9592T>C)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

BRCA2 p.Cys3198Arg

c.9592T>C · rs80359229 · VCV38252

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.167	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.053	GERP 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	6.358	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 0.0148% European (non-Finnish) · 175/1,179,990 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.011% 178/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0148%	6,743
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	59,990

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.Cys3198Arg
Coding: c.9592T>C
MANE Select: NM_000059
dbSNP: rs80359229
Type: single nucleotide variant
Location: chr13:32396988 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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 Fanconi anemia complementation group D1 hereditary neoplastic syndrome prostate cancer, hereditary

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Cys3198= Likely benign ★★★ same residue
BRCA2 p.Cys3198Ser Uncertain significance ★ ⚠ same residue
BRCA2 p.Cys3198Tyr Conflicting classifications of pathogenicity ★ ⚠ 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
BRCA2 c.475+1G>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-cys3198arg (accessed [today's date]).

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