Is BRCA1 p.Trp1718Leu (c.5153G>T) pathogenic?

BRCA1 p.Trp1718Leu (c.5153G>T) is classified Uncertain significance in BRCA1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-03-01). AlphaMissense: likely pathogenic (0.847); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA1 p.Trp1718Leu (c.5153G>T)?

BRCA1 p.Trp1718Leu (c.5153G>T) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Trp1718Leu (c.5153G>T) in the general population?

BRCA1 p.Trp1718Leu (c.5153G>T) is absent from gnomAD v4.1 (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.

What do computational predictors say about BRCA1 p.Trp1718Leu (c.5153G>T)?

AlphaMissense predicts likely pathogenic (score 0.847) — an in-silico prediction, not a clinical call.

BRCA1 p.Trp1718Leu

c.5153G>T · rs41293461 · VCV632609

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.847	likely pathogenic · top 4% in BRCA1
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Trp1718Leu
Coding: c.5153G>T
MANE Select: NM_007294
dbSNP: rs41293461
Type: single nucleotide variant
Location: chr17:43063373 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1718: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally impaired in vitro); an α-helix

Full BRCA1 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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Trp1718Gly Likely pathogenic ★★★ same residue
BRCA1 p.Trp1718Ter Pathogenic ★★★ same residue
BRCA1 p.Trp1718Ser Uncertain significance ★★★ ⚠ same residue
BRCA1 p.Trp1718Cys Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Trp1718fs Pathogenic same residue
BRCA1 p.Trp1718Arg Uncertain significance ★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>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/brca1-p-trp1718leu (accessed [today's date]).

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