Is BRIP1 p.Ile504fs (c.1510dup) pathogenic?

BRIP1 p.Ile504fs (c.1510dup) is classified Pathogenic in BRIP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-01-26). Very rare (popmax 0.000678%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Ile504fs (c.1510dup)?

BRIP1 p.Ile504fs (c.1510dup) is associated with hereditary neoplastic syndrome, ovarian cancer, Fanconi anemia complementation group J (ClinVar).

How common is BRIP1 p.Ile504fs (c.1510dup) in the general population?

BRIP1 p.Ile504fs (c.1510dup) is very rare (popmax 0.000678%, nfe) (gnomAD).

BRIP1 p.Ile504fs

c.1510dup · rs775735278 · VCV230237

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, 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 11 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 0.76, phastCons 0.019

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,552 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000616% 9/1,461,194 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)grpmax	0.000678%	147,444

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BRIP1
Protein: p.Ile504fs
Coding: c.1510dup
MANE Select: NM_032043
dbSNP: rs775735278
Type: Duplication
Location: chr17:61784387 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB

Full BRIP1 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: ovarian cancer Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 p.Ile504Met Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile504Thr Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile504= Benign/Likely benign ★★ same residue
BRIP1 c.2492+2dup Pathogenic/Likely pathogenic ★★ same condition
BRIP1 p.Ala27fs Pathogenic/Likely pathogenic ★★ same condition
BRIP1 p.Ala551fs Pathogenic ★★ same condition
BRIP1 p.Ala759fs Pathogenic/Likely pathogenic ★★ same condition
BRIP1 p.Ala841fs 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/brip1-p-ile504fs (accessed [today's date]).

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