Is BRCA2 p.Ala938Profs (c.2808_2811del) pathogenic?

BRCA2 p.Ala938Profs (c.28082811del) is classified Pathogenic in BRCA2 (ClinVar, Expert panel, 68 submitters; last evaluated 2016-04-22). Very rare (popmax 0.00229%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ala938Profs (c.2808_2811del)?

BRCA2 p.Ala938Profs (c.2808_2811del) is associated with breast-ovarian cancer, familial, susceptibility to, 2, gastric cancer, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Ala938Profs (c.2808_2811del) in the general population?

BRCA2 p.Ala938Profs (c.2808_2811del) is very rare (popmax 0.00229%, nfe) (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 p.Ala938Profs

c.2808_2811del · rs80359351 · VCV9322

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 68 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3	GERP -4.5
Overall
CADD	25.1	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 0.00229% European (non-Finnish) · 27/1,179,892 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00204% 33/1,613,768 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)grpmax	0.00229%	43,700
East Asian	0.00223%	44,834
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	74,934
South Asian	0.0011%	91,056

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala938Profs
Coding: c.2808_2811del
MANE Select: NM_000059
dbSNP: rs80359351
Type: Deletion
Location: chr13:32337161 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 938: the 'interaction with npm1' region

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

Also linked: gastric cancer hereditary breast ovarian cancer syndrome uterine corpus cancer breast cancer medulloblastoma Wilms tumor 1 breast-ovarian cancer, familial, susceptibility to, 1 Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma breast neoplasm BRCA2-related cancer predisposition prostate cancer, hereditary

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ala938fs Pathogenic ★ same residue
BRCA2 p.Ala938Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala938Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 c.316+4del Pathogenic ★★★ same condition
BRCA2 c.5217_5224del Pathogenic ★★★ same condition
BRCA2 c.68-?_316+?del Pathogenic ★★★ same condition
BRCA2 c.7008-?_7805+?del Pathogenic ★★★ same condition
BRCA2 c.7980_7984delTGATA 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-ala938profs (accessed [today's date]).

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