Is BRCA2 c.8953+80G>A pathogenic?

BRCA2 c.8953+80G>A is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-05). Ultra-rare (popmax 0.0838%, sas); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 c.8953+80G>A?

BRCA2 c.8953+80G>A is associated with breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 c.8953+80G>A in the general population?

BRCA2 c.8953+80G>A is ultra-rare (popmax 0.0838%, sas) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

BRCA2 c.8953+80G>A

rs543831222 · VCV1327148

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0838%, sas)

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +80	deep intronic (+80 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -4.2
Non-coding constraint	Z 1.98	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	0.509	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0838% South Asian · 72/85,890 alleles

Filtering AF 0.0682% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0625%

Overall 0.00962% 149/1,549,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0838%	1,193
Middle Eastern	0.0706%	1,416
Admixed American	0.0144%	6,952
Remaining individualsnot grpmax-eligible	0.01%	9,995
European (non-Finnish)	0.00502%	19,908
East Asian	0.00232%	43,180
African / African-American	0.00138%	72,262

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
Coding: c.8953+80G>A
MANE Select: NM_000059
dbSNP: rs543831222
Type: single nucleotide variant
Location: chr13:32379595 (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

breast-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C Pathogenic ★★★ same condition
BRCA2 c.475+1G>A Pathogenic ★★★ same condition
BRCA2 c.475+1G>T Pathogenic ★★★ same condition
BRCA2 c.476-2A>G Pathogenic ★★★ same condition
BRCA2 c.517-2A>G 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-c-8953-plus-80g-a (accessed [today's date]).

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