Is BRCA2 p.Lys2128= (c.6384A>G) pathogenic?

BRCA2 p.Lys2128= (c.6384A>G) is classified Likely benign in BRCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-30). Very rare (popmax 0.00446%, eas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Lys2128= (c.6384A>G)?

BRCA2 p.Lys2128= (c.6384A>G) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Lys2128= (c.6384A>G) in the general population?

BRCA2 p.Lys2128= (c.6384A>G) is very rare (popmax 0.00446%, 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.Lys2128=

c.6384A>G · rs397507847 · VCV482979

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary breast ovarian cancer syndrome

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 0.57	GERP -3, phastCons 0.81
Overall
CADD	1.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,798 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000187% 3/1,606,530 alleles · very rare exomes 3/1,454,182 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,399
European (non-Finnish)	8.49e-05%	1,178,138

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.Lys2128=
Coding: c.6384A>G
MANE Select: NM_000059
dbSNP: rs397507847
Type: single nucleotide variant
Location: chr13:32340739 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2128: a UniProt-annotated variant site (in bc)

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: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Lys2128Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Lys2128Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Lys2128Asn Likely benign ★ same residue
BRCA2 p.Lys2128fs Pathogenic ★ same residue
BRCA2 p.Lys2128Ter Pathogenic ★★★ 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

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-lys2128 (accessed [today's date]).

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