Is BRCA2 p.Tyr688Cys (c.2063A>G) pathogenic?

BRCA2 p.Tyr688Cys (c.2063A>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.08); Very rare (popmax 0.0011%, sas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Tyr688Cys (c.2063A>G)?

BRCA2 p.Tyr688Cys (c.2063A>G) is associated with hereditary breast ovarian cancer syndrome, melanoma, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Tyr688Cys (c.2063A>G) in the general population?

BRCA2 p.Tyr688Cys (c.2063A>G) is very rare (popmax 0.0011%, sas) (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.Tyr688Cys (c.2063A>G)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

BRCA2 p.Tyr688Cys

c.2063A>G · rs28897713 · VCV523315

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.31	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -4.5, phastCons 0.044
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	9.21	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 0.0011% South Asian · 1/90,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,408 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,992
European (non-Finnish)	0.00017%	589,925

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.Tyr688Cys
Coding: c.2063A>G
MANE Select: NM_000059
dbSNP: rs28897713
Type: single nucleotide variant
Location: chr13:32336418 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 688: the 'interaction with npm1' region

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: melanoma hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Tyr688Ter Pathogenic ★★★ same residue
BRCA2 p.Tyr688Asp Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Tyr688Phe Uncertain significance ★ ⚠ same residue
BRCA2 p.Tyr688= Likely benign ★ 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

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-tyr688cys (accessed [today's date]).

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