Is BRCA2 p.His2147Gln (c.6441C>G) pathogenic?

BRCA2 p.His2147Gln (c.6441C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-05-15). AlphaMissense: likely benign (0.1038); Very rare (popmax 0.000767%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.His2147Gln (c.6441C>G)?

BRCA2 p.His2147Gln (c.6441C>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.His2147Gln (c.6441C>G) in the general population?

BRCA2 p.His2147Gln (c.6441C>G) is very rare (popmax 0.000767%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.His2147Gln (c.6441C>G)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

BRCA2 p.His2147Gln

c.6441C>G · rs80358879 · VCV38045

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000767%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.456	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.6
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	0.009	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 0.000767% European (non-Finnish) · 9/1,174,002 alleles

Filtering AF 0.000361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000565% 9/1,593,960 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.His2147Gln
Coding: c.6441C>G
MANE Select: NM_000059
dbSNP: rs80358879
Type: single nucleotide variant
Location: chr13:32340796 (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

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

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

Similar variants

BRCA2 p.His2147= Likely benign ★★★ same residue
BRCA2 p.His2147Arg Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.His2147Tyr Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.His2147fs Pathogenic/Likely pathogenic ★★ same residue
BRCA2 p.His2147_Ser2148insTer 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-his2147gln (accessed [today's date]).

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