Is BRCA1 p.Leu1340Ter (c.4019T>A) pathogenic?

BRCA1 p.Leu1340Ter (c.4019T>A) is classified Pathogenic/Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Leu1340Ter (c.4019T>A)?

BRCA1 p.Leu1340Ter (c.4019T>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Leu1340Ter (c.4019T>A) in the general population?

BRCA1 p.Leu1340Ter (c.4019T>A) is absent from gnomAD v4.1 (gnomAD).

BRCA1 p.Leu1340Ter

c.4019T>A · rs2053483708 · VCV993165

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic 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 10 of 23
REVEL	0.016	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.28, phastCons 0.14
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA1
Protein: p.Leu1340Ter
Coding: c.4019T>A
MANE Select: NM_007294
dbSNP: rs2053483708
Type: single nucleotide variant
Location: chr17:43091512 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1340: a UniProt-annotated variant site (in fancs); the 'disordered' region

Full BRCA1 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 ovarian cancer syndrome

Similar variants

BRCA1 p.Leu1340= Likely benign ★★★ same residue
BRCA1 p.Leu1340Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G Pathogenic ★★★ same condition
BRCA1 c.213-12A>G 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/brca1-p-leu1340ter (accessed [today's date]).

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