Is BRCA2 p.Glu1608Ter (c.4822G>T) pathogenic?

BRCA2 p.Glu1608Ter (c.4822G>T) is classified Likely pathogenic in BRCA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-10-02). Very rare (popmax 0.00223%, eas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Glu1608Ter (c.4822G>T)?

BRCA2 p.Glu1608Ter (c.4822G>T) is associated with hereditary breast ovarian cancer syndrome, gastric cancer (ClinVar).

How common is BRCA2 p.Glu1608Ter (c.4822G>T) in the general population?

BRCA2 p.Glu1608Ter (c.4822G>T) is very rare (popmax 0.00223%, eas) (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.Glu1608Ter

c.4822G>T · rs1566231194 · VCV632719

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.33, phastCons 0.11
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 6.84e-05% 1/1,461,574 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.Glu1608Ter
Coding: c.4822G>T
MANE Select: NM_000059
dbSNP: rs1566231194
Type: single nucleotide variant
Location: chr13:32339177 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1608: the 'interaction with rad51' region; the 'interaction with polh' 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: gastric cancer

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Glu1608Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Glu1608fs Pathogenic ★★★ same residue
BRCA2 p.Glu1608Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C Pathogenic ★★★ same condition
BRCA2 c.475+1G>A Pathogenic ★★★ same condition
BRCA2 c.475+1G>T 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-glu1608ter (accessed [today's date]).

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