Is BRCA2 p.Ser3366Ter (c.10095_10096insT) pathogenic?

BRCA2 p.Ser3366Ter (c.1009510096insT) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0381%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ser3366Ter (c.10095_10096insT)?

BRCA2 p.Ser3366Ter (c.10095_10096insT) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ser3366Ter (c.10095_10096insT) in the general population?

BRCA2 p.Ser3366Ter (c.10095_10096insT) is ultra-rare (popmax 0.0381%, nfe) (gnomAD).

BRCA2 p.Ser3366Ter

c.10095_10096insT · rs730881599 · VCV440455

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (27 of 27) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP -1.5, phastCons 0.004
Overall
CADD	24.5	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 0.0381% European (non-Finnish) · 450/1,180,030 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.0311% 502/1,614,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0453%	2,208
European (non-Finnish)grpmax	0.0381%	2,622
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
Admixed American	0.00167%	60,024
African / African-American	0.00133%	75,040
South Asian	0.0011%	91,068

Finnish 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.Ser3366Ter
Coding: c.10095_10096insT
MANE Select: NM_000059
dbSNP: rs730881599
Type: Insertion
Location: chr13:32398608 (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.Ser3366delinsAsnTyrIleTer Benign/Likely benign ★★ same residue
BRCA2 p.Ser3366Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Ser3366Asn Uncertain significance ★ ⚠ same residue
BRCA2 p.Ser3366fs Likely benign ★ same residue
BRCA2 c.156_157insAlu Pathogenic ★★★ same condition
BRCA2 p.Ala1327fs Pathogenic ★★★ same condition
BRCA2 p.Ala1411fs Pathogenic ★★★ same condition
BRCA2 p.Ala1825fs 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-ser3366ter (accessed [today's date]).

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