Is BARD1 p.Lys540fs (c.1620del) pathogenic?

BARD1 p.Lys540fs (c.1620del) is classified Pathogenic in BARD1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-16). Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BARD1 p.Lys540fs (c.1620del)?

BARD1 p.Lys540fs (c.1620del) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Lys540fs (c.1620del) in the general population?

BARD1 p.Lys540fs (c.1620del) is very rare (popmax 0.000254%, nfe) (gnomAD).

BARD1 p.Lys540fs

c.1620del · rs1693504040 · VCV849559

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 0.54, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,818 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,504 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: BARD1
Protein: p.Lys540fs
Coding: c.1620del
MANE Select: NM_000465
dbSNP: rs1693504040
Type: Deletion
Location: chr2:214752504 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 540: an α-helix

Full BARD1 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 carcinoma

Similar variants

BARD1 p.Lys540Asn Uncertain significance ★★ ⚠ same residue
BARD1 p.Lys540= Likely benign ★★ same residue
BARD1 p.Lys540Arg Uncertain significance ★ ⚠ same residue
BARD1 c.1306_1314+7del Likely pathogenic ★★ same condition
BARD1 c.158+2_158+10del Likely pathogenic ★★ same condition
BARD1 c.1676_1677+23del Likely pathogenic ★★ same condition
BARD1 c.1678-1_1678del Likely pathogenic ★★ same condition
BARD1 c.1865_1903+274del Likely 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/bard1-p-lys540fs (accessed [today's date]).

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