Is BRCA2 p.Pro606Ser (c.1816C>T) pathogenic?

BRCA2 p.Pro606Ser (c.1816C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-12). AlphaMissense: likely benign (0.0871); Very rare (popmax 0.00135%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Pro606Ser (c.1816C>T)?

BRCA2 p.Pro606Ser (c.1816C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Pro606Ser (c.1816C>T) in the general population?

BRCA2 p.Pro606Ser (c.1816C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Pro606Ser (c.1816C>T)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro606Ser

c.1816C>T · rs765924757 · VCV495434

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.22	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 0.81	GERP 0.52
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	13.67	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 0.00135% African / African-American · 1/74,210 alleles

Overall 0.000125% 2/1,605,136 alleles · very rare exomes 2/1,452,994 · genomes 0/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,210
European (non-Finnish)	8.49e-05%	1,177,550

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.Pro606Ser
Coding: c.1816C>T
MANE Select: NM_000059
dbSNP: rs765924757
Type: single nucleotide variant
Location: chr13:32333294 (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

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

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Pro606= Likely benign ★★★ same residue
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.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-pro606ser (accessed [today's date]).

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