Is BRCA2 p.Pro606= (c.1818G>A) pathogenic?

BRCA2 p.Pro606= (c.1818G>A) is classified Likely benign in BRCA2 (ClinVar, Expert panel, 16 submitters; last evaluated 2017-06-29). Ultra-rare (popmax 0.0166%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Pro606= (c.1818G>A)?

BRCA2 p.Pro606= (c.1818G>A) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Pro606= (c.1818G>A) in the general population?

BRCA2 p.Pro606= (c.1818G>A) is ultra-rare (popmax 0.0166%, mid) (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.

BRCA2 p.Pro606=

c.1818G>A · rs76844014 · VCV183776

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.09	GERP -3.3
Overall
CADD	6.992	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,020 alleles

Filtering AF 0.00693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00534%

Overall 0.00156% 25/1,604,782 alleles · ultra-rare exomes 23/1,452,872 · genomes 2/151,910 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,020
South Asian	0.0124%	8,069
East Asian	0.00446%	22,417
Admixed American	0.00346%	28,898
Finnishnot grpmax-eligible	0.00157%	63,616
African / African-American	0.00135%	74,022
European (non-Finnish)	0.000594%	168,220

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.Pro606=
Coding: c.1818G>A
MANE Select: NM_000059
dbSNP: rs76844014
Type: single nucleotide variant
Location: chr13:32333296 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 606: a UniProt-annotated variant site (in)

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 breast cancer 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.Pro606Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro606fs Pathogenic ★★★ same residue
BRCA2 p.Pro606_Lys607delinsLeuTer Pathogenic/Likely pathogenic ★★ same residue

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-pro606 (accessed [today's date]).

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