Is BRIP1 p.Leu340Phe (c.1018C>T) pathogenic?

BRIP1 p.Leu340Phe (c.1018C>T) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1869); Ultra-rare (popmax 0.0245%, eas); Associated with familial ovarian cancer.

What condition is associated with BRIP1 p.Leu340Phe (c.1018C>T)?

BRIP1 p.Leu340Phe (c.1018C>T) is associated with familial ovarian cancer, Fanconi anemia complementation group J, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Leu340Phe (c.1018C>T) in the general population?

BRIP1 p.Leu340Phe (c.1018C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about BRIP1 p.Leu340Phe (c.1018C>T)?

AlphaMissense predicts likely benign (score 0.1869) — an in-silico prediction, not a clinical call.

BRIP1 p.Leu340Phe

c.1018C>T · rs755796609 · VCV407835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1869	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -12.80	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.0245% East Asian · 11/44,862 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000805% 13/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,078
Remaining individualsnot grpmax-eligible	0.0032%	31,251

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.Leu340Phe
Coding: c.1018C>T
MANE Select: NM_032043
dbSNP: rs755796609
Type: single nucleotide variant
Location: chr17:61801375 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 340: the helicase atp-binding domain

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

Disease context

familial ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group J hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRIP1 p.Leu340Pro Uncertain significance ★★ ⚠ same residue
BRIP1 p.Leu340= Likely benign ★ same residue
BRIP1 p.Leu340fs Pathogenic/Likely pathogenic ★★ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>T Likely pathogenic ★★ same condition
BRIP1 c.1340+1G>A 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-leu340phe (accessed [today's date]).

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