Is BRCA2 p.Pro655Arg (c.1964C>G) pathogenic?

BRCA2 p.Pro655Arg (c.1964C>G) is classified Benign in BRCA2 (ClinVar, Expert panel, 33 submitters; last evaluated 2015-08-10). AlphaMissense: likely benign (0.1374); Very rare (popmax 0.00936%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Pro655Arg (c.1964C>G)?

BRCA2 p.Pro655Arg (c.1964C>G) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 p.Pro655Arg (c.1964C>G) in the general population?

BRCA2 p.Pro655Arg (c.1964C>G) is very rare (popmax 0.00936%, 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.Pro655Arg (c.1964C>G)?

AlphaMissense predicts likely benign (score 0.1374) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro655Arg

c.1964C>G · rs28897712 · VCV37770

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 33 submitters

AlphaMissense

likely benign

0.1374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.1374	likely benign
REVEL	0.15	moderately 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 -0.21	GERP -3.8
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	12.75	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 0.00936% European (non-Finnish) · 110/1,174,692 alleles

Filtering AF 0.00794% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00739%

Overall 0.0536% 858/1,601,692 alleles · very rare exomes 777/1,449,538 · genomes 81/152,154 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.27%	44
Remaining individualsnot grpmax-eligible	0.136%	736
European (non-Finnish)grpmax	0.00936%	10,679
Admixed American	0.00519%	19,283
African / African-American	0.00405%	24,705

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro655Arg
Coding: c.1964C>G
MANE Select: NM_000059
dbSNP: rs28897712
Type: single nucleotide variant
Location: chr13:32336319 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 655: the 'interaction with npm1' 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 prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Pro655Ala Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro655Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro655Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro655Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro655Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro655= Likely benign ★ same residue
BRCA2 p.Pro655fs Pathogenic ★★★ 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-pro655arg (accessed [today's date]).

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