Is BRCA2 p.Pro201Leu (c.602C>T) pathogenic?

BRCA2 p.Pro201Leu (c.602C>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-10). AlphaMissense: likely pathogenic (0.5984); Very rare (popmax 0.00133%, afr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Pro201Leu (c.602C>T)?

BRCA2 p.Pro201Leu (c.602C>T) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Pro201Leu (c.602C>T) in the general population?

BRCA2 p.Pro201Leu (c.602C>T) is very rare (popmax 0.00133%, afr) (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.Pro201Leu (c.602C>T)?

AlphaMissense predicts likely pathogenic (score 0.5984) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro201Leu

c.602C>T · rs397507822 · VCV425026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.5984	likely pathogenic · top 7% in BRCA2
REVEL	0.364	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	24.0	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 0.00133% African / African-American · 1/74,988 alleles

Overall 0.000124% 2/1,610,948 alleles · very rare exomes 2/1,458,672 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,988
European (non-Finnish)	8.5e-05%	1,177,126

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.Pro201Leu
Coding: c.602C>T
MANE Select: NM_000059
dbSNP: rs397507822
Type: single nucleotide variant
Location: chr13:32326584 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 201: an α-helix; a UniProt-annotated variant site (in bc)

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

Disease context

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

Also linked: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Pro201Ala Uncertain significance ★★ same residue
BRCA2 p.Pro201Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro201Thr Uncertain significance ★ same residue
BRCA2 p.Pro201= Likely benign ★ same residue
BRCA2 p.Pro201Arg Uncertain significance ★ 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

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-pro201leu (accessed [today's date]).

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