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NM_000059.4:c.6698C>T
p.Ala2233Val · BRCA2
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2 · v1.2
0%
complete
Final classification
VUS
BP1
BRCA2
c.6698C>T
p.Ala2233Val
missense · exon 11
Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

This missense change affects BRCA2, a tumor-suppressor gene whose DNA double-strand-break repair function supports genome stability and whose inherited loss of function causes hereditary breast and ovarian cancer syndrome.

Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.6698C>T
GRCh38
chr13:32341053 C>T
GRCh37
chr13:32915190 C>T
VUS: BP1 (Strong) is the only applied criterion and does not satisfy ENIGMA's Likely Benign combination rule without additional benign evidence.
Classification rationale
BP1 VUS
BRCA2 c.6698C>T missense · exon 11

VUS: BP1 (Strong) is supported by residue 2233 being outside BRCA2 critical domains and SpliceAI maximum delta 0.014 indicating no predicted splicing impact.

BP1 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_000059.4 · variants mapped to exon structure
BRCA2 NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
BP1 strong Benign
Met, Strong: residue 2233 is outside BRCA2 critical domains and SpliceAI max delta 0.014 is below the <=0.1 no-splicing threshold.
ENIGMA BP1_Strong requires a missense variant outside a potentially clinically important functional domain with SpliceAI <=0.1; missense prediction is not applicable.BRCA2 residue 2233 is outside the governing PALB2-binding domain at aa 10-40 and DNA-binding domain at aa 2481-3186.SpliceAI maximum delta score is 0.014, below the ENIGMA <=0.1 no-splicing threshold.
cspec ↗spliceai ↗
Assessed · not applied · 5 not met · 10 not assessed
Pathogenic
PS1 Not met: no established pathogenic comparator producing p.Ala2233Val was identified, while the documented alternate p.Ala2233Asp is benign or uncertain.
PS3 Not assessed: ENIGMA Table 9 contains no calibrated PS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V.
PS4 Not assessed: no exact-variant case-control p-value, OR, or confidence interval was available to test p <=0.05, OR >=4, and lower confidence interval >2.0.
PM2 Not assessed: the variant is absent from required non-cancer gnomAD subsets, but the ENIGMA PM2 rule requires regional read depth >=25 and no depth value is available.
PM3 Not assessed: no documented Fanconi-anemia phenotype or phased pathogenic BRCA2 variant in trans/cis is available for PM3 scoring.
PP1 Not assessed: no affected-relative genotypes or co-segregation LR are available, so the PP1 threshold of LR >=2.08 cannot be evaluated.
PP3 Not met: REVEL 0.555 is below the >=0.644 supporting PP3 threshold and remains in the non-informative gray zone.
PP4 Not assessed: no exact-variant combined clinical LR was available to test PP4 thresholds of >=2.08, >=4.3, >=18.7, or >=350.
Benign
BA1 Not met: the variant is absent from required non-cancer gnomAD subsets, far below the ENIGMA BA1 threshold of FAF >0.001.
BS1 Not met: the variant is absent from required non-cancer gnomAD subsets, below both ENIGMA BS1 thresholds of FAF >0.00002 and >0.0001.
BS2 Not assessed: no qualifying patient-level homozygote or trans co-occurrence with age and Fanconi-anemia phenotype data is available for BS2 point scoring.
BS3 Not assessed: ENIGMA Table 9 contains no calibrated BS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V.
BS4 Not assessed: no affected-relative non-segregation data or benign-direction LR are available, so the BS4 threshold of LR <=0.48 cannot be evaluated.
BP4 Not met: REVEL 0.555 exceeds the <=0.29 supporting BP4 threshold and is therefore a gray-zone missense result.
BP5 Not assessed: no exact-variant combined LR was available to test BP5's benign-direction thresholds of <=0.48, <=0.23, <=0.05, or <=0.00285.
N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 409574)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.555. BayesDel score = 0.0812715.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66448396, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR
31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR
19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR
23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR