Is BRIP1 p.Thr48fs (c.141del) pathogenic?

BRIP1 p.Thr48fs (c.141del) is classified Pathogenic/Likely pathogenic in BRIP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-25). Very rare (popmax 0.00133%, afr); Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Thr48fs (c.141del)?

BRIP1 p.Thr48fs (c.141del) is associated with hereditary breast carcinoma, Fanconi anemia complementation group J, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Thr48fs (c.141del) in the general population?

BRIP1 p.Thr48fs (c.141del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

BRIP1 p.Thr48fs

c.141del · rs587782065 · VCV141861

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary breast carcinoma

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 3 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Overall
CADD	22.5	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 0.00133% African / African-American · 1/74,922 alleles

Overall 0.000657% 1/152,206 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: BRIP1
Protein: p.Thr48fs
Coding: c.141del
MANE Select: NM_032043
dbSNP: rs587782065
Type: Deletion
Location: chr17:61859860 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 48: the helicase atp-binding domain

Full BRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group J hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRIP1 p.Thr48Lys Uncertain significance ★★ ⚠ same residue
BRIP1 p.Thr48= Benign/Likely benign ★★ same residue
BRIP1 p.Thr48Ala Uncertain significance ★ ⚠ same residue
BRIP1 p.Thr48Arg Uncertain significance ★ ⚠ same residue
BRIP1 p.Thr48Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 c.1629-3_1634del Likely pathogenic ★★ same condition
BRIP1 c.1936del Pathogenic ★★ same condition
BRIP1 c.205+1del Pathogenic/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/brip1-p-thr48fs (accessed [today's date]).

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