Is BRIP1 p.Lys705fs (c.2114_2118del) pathogenic?

BRIP1 p.Lys705fs (c.21142118del) is classified Pathogenic/Likely pathogenic in BRIP1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-19). Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Lys705fs (c.2114_2118del)?

BRIP1 p.Lys705fs (c.2114_2118del) is associated with hereditary neoplastic syndrome, breast cancer, ovarian cancer (ClinVar).

How common is BRIP1 p.Lys705fs (c.2114_2118del) in the general population?

BRIP1 p.Lys705fs (c.2114_2118del) is very rare (popmax 0.00267%, afr) (gnomAD).

BRIP1 p.Lys705fs

c.2114_2118del · rs864622611 · VCV220629

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 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	predicted	premature termination codon in exon 15 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Overall
CADD	34.0	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

Grpmax group 0.00267% African / African-American · 2/74,856 alleles

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

Overall 0.000186% 3/1,613,288 alleles · very rare exomes 0/1,461,292 · genomes 3/151,996 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,428
Admixed American	0.00167%	59,976

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.Lys705fs
Coding: c.2114_2118del
MANE Select: NM_032043
dbSNP: rs864622611
Type: Deletion
Location: chr17:61744571 (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: breast cancer ovarian cancer Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 c.1629-3_1634del Likely pathogenic ★★ same condition
BRIP1 c.1936del Pathogenic ★★ same condition
BRIP1 c.205+1del Pathogenic/Likely pathogenic ★★ same condition
BRIP1 c.2257+2_2257+8del Likely pathogenic ★★ same condition
BRIP1 c.2370_2379+20del Likely pathogenic ★★ same condition
BRIP1 c.2492_2492+5del Likely pathogenic ★★ same condition
BRIP1 c.2492+1del Likely pathogenic ★★ same condition
BRIP1 c.628-5_629del 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-lys705fs (accessed [today's date]).

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