Is BRIP1 p.Ile983fs (c.2947dup) pathogenic?

BRIP1 p.Ile983fs (c.2947dup) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-26). Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Ile983fs (c.2947dup)?

BRIP1 p.Ile983fs (c.2947dup) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Ile983fs (c.2947dup) in the general population?

BRIP1 p.Ile983fs (c.2947dup) is very rare (popmax 0.00267%, afr) (gnomAD).

BRIP1 p.Ile983fs

c.2947dup · rs774684620 · VCV407863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	escapes	premature termination codon in the last exon (20 of 20) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.64	GERP -2.3
Overall
CADD	24.8	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

Grpmax group 0.00267% African / African-American · 2/74,944 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,492 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,472
Admixed American	0.00167%	59,938
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	90,874
European (non-Finnish)	0.00017%	589,904

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.Ile983fs
Coding: c.2947dup
MANE Select: NM_032043
dbSNP: rs774684620
Type: Duplication
Location: chr17:61684098 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 983: the 'interaction with brca1' region

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: Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 p.Ile983Met Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile983Phe Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile983Val Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ile983Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Ile983Thr Conflicting classifications of pathogenicity ★ ⚠ 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

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-ile983fs (accessed [today's date]).

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