Is BRCA2 p.Gln147Leu (c.440A>T) pathogenic?

BRCA2 p.Gln147Leu (c.440A>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2026); Very rare (popmax 0.0011%, nfe); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Gln147Leu (c.440A>T)?

BRCA2 p.Gln147Leu (c.440A>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Gln147Leu (c.440A>T) in the general population?

BRCA2 p.Gln147Leu (c.440A>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Gln147Leu (c.440A>T)?

AlphaMissense predicts likely benign (score 0.2026) — an in-silico prediction, not a clinical call.

BRCA2 p.Gln147Leu

c.440A>T · rs80358674 · VCV37900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.2026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.2026	likely benign
REVEL	0.183	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -4.5
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	10.97	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,178,316 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000807% 13/1,610,194 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: BRCA2
Protein: p.Gln147Leu
Coding: c.440A>T
MANE Select: NM_000059
dbSNP: rs80358674
Type: single nucleotide variant
Location: chr13:32326115 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRCA2 p.Gln147Ter Pathogenic ★★★ same residue
BRCA2 p.Gln147= Likely benign ★★★ same residue
BRCA2 p.Gln147Arg Benign ★★★ same residue
BRCA2 p.Gln147His Uncertain significance ★★ ⚠ same residue
BRCA2 p.Gln147fs Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A 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/brca2-p-gln147leu (accessed [today's date]).

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