Is BRCA2 p.Tyr688= (c.2064T>C) pathogenic?

BRCA2 p.Tyr688= (c.2064T>C) is classified Likely benign in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). Very rare (popmax 0.0022%, sas).

How common is BRCA2 p.Tyr688= (c.2064T>C) in the general population?

BRCA2 p.Tyr688= (c.2064T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

BRCA2 p.Tyr688=

c.2064T>C · rs80358485 · VCV2576466

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -3.5, phastCons 0.99
Overall
CADD	5.064	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,004 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,432 alleles · very rare

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.Tyr688=
Coding: c.2064T>C
MANE Select: NM_000059
dbSNP: rs80358485
Type: single nucleotide variant
Location: chr13:32336419 (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

Similar variants

BRCA2 p.Tyr688Ter Pathogenic ★★★ same residue
BRCA2 p.Tyr688Asp Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Tyr688Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Tyr688Phe Uncertain significance ★ ⚠ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same type
BRCA2 c.316+2T>C Pathogenic ★★★ same type
BRCA2 c.316+5G>A Pathogenic ★★★ same type
BRCA2 c.316+5G>C Pathogenic ★★★ same type

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-tyr688 (accessed [today's date]).

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