Final classification

Likely Benign

PP3BS3

BRCA2

c.7484T>C

p.Ile2495Thr

missense · exon 15

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

BRCA2 encodes a tumor-suppressor DNA-repair protein whose reduced or altered activity contributes to hereditary breast and ovarian cancer syndrome and related tumor risks.

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.7484T>C

GRCh38

chr13:32356476 T>C

GRCh37

chr13:32930613 T>C

Likely Benign: ENIGMA assigns BS3 Strong and PP3 Supporting; the net conflicting-evidence score is −3, within the Likely Benign range.

Classification rationale

PP3 BS3 Likely Benign

BRCA2 c.7484T>C missense · exon 15

Likely Benign: BS3 Strong is assigned from two calibrated neutral functional studies. PP3 Supporting: REVEL 0.663 exceeds the 0.644 supporting threshold. Likely Benign: ENIGMA's conflicting-evidence score is −3 (BS3 −4 plus PP3 +1).

PP3 + BS3 → Likely Benign

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 · 2 applied · 14 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 · 2

Strength Supporting Moderate Strong Very strong

PP3 supporting Pathogenic

Met, Supporting: REVEL 0.663 meets the ClinGen SVI PP3 supporting threshold of 0.644 for missense variants.

The ENIGMA BRCA1/2 V1.2 specification defines PP3 for predicted deleterious computational impact and identifies the BRCA2 DNA-binding domain as a clinically important functional domain.The case-specific REVEL lookup reports a score of 0.663 for BRCA2 c.7484T>C (p.Ile2495Thr).The supplied ClinGen SVI REVEL calibration assigns PP3 Supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).

cspec ↗

BS3 strong Benign

Met, Strong: ENIGMA Table 9 assigns BS3 Strong from two calibrated neutral studies, including Mesman results of 58% HDR and 84% cisplatin sensitivity versus wild type.

Specifications_Table9_V1.2_2024-11-18.xlsx: the exact c.7484T>C / p.(Ile2495Thr) row pre-assigns BS3 Strong and records two calibrated studies, Mesman 2019 (PMID:29988080) and Richardson 2021 (PMID:33609447), with benign/neutral functional results.Mesman et al. (PMID:29988080), Table 2 and Fig. 3b: c.7484T>C p.Ile2495Thr complemented the mESC phenotype after endogenous Brca2 loss; HDR was 58% and cisplatin sensitivity was 84% relative to wild type.ENIGMA Appendix E states that PS3 and BS3 are reserved for protein-function assays, that the selected mammalian assays were calibrated against clinically classified reference variants, and that no functional impact without conflicting damaging evidence supports Strong benign evidence.

cspec ↗PMID:29988080 ↗

Assessed · not applied · 9 not met · 5 not assessed

Pathogenic

PS1 Not met: no qualifying pathogenic variant producing the same Ile2495Thr amino-acid change was identified in the governing VCEP materials.

PS3 Not met: ENIGMA Table 9 assigns BS3 Strong after two calibrated studies found no damaging effect, including 58% HDR and 84% cisplatin sensitivity in Mesman et al.

PS4 Not assessed: the exact variant row lacks a qualifying PS4 case-control OR and p-value, and ENIGMA prohibits using its two observations as proband-counting evidence.

PM2 Not met: the variant is observed in both required non-cancer datasets, with 2 alleles in v2.1 exomes and 1 allele in v3.1 genomes.

PM3 Not assessed: no documented Fanconi anemia phenotype, qualifying BRCA2 co-occurring pathogenic variant, or phase information supports ENIGMA PM3 points.

PP1 Not assessed: the exact variant row has no segregation LR, and no quantitative co-segregation result or meiosis count is available for comparison with PP1 LR ≥2.08.

PP5 Not met: ClinVar has no exact-variant expert-panel classification; its available submissions are single-laboratory assertions, not eligible PP5 evidence.

Benign

BA1 Not met: maximum required non-cancer filter allele frequency was 3.23e-06, below the ENIGMA BA1 threshold of >0.001.

BS1 Not met: maximum required non-cancer filter allele frequency was 3.23e-06, below the ENIGMA BS1 Supporting threshold of >0.00002.

BS2 Not assessed: gnomAD reports zero homozygotes, but no qualifying phenotyped healthy-adult or clinical-cohort BS2 observations are available.

BS4 Not assessed: the exact variant row has no segregation LR, and the available combined LR 0.7333 is above the BS4 supporting threshold of ≤0.48.

BP1 Not met: Ile2495 lies inside the ENIGMA DNA-binding domain 2481-3186, whereas BP1 requires a missense variant outside a clinically important domain.

BP4 Not met: REVEL 0.663 exceeds the ClinGen SVI BP4 supporting threshold of <=0.29 for missense variants.

BP6 Not met: ClinVar has no exact-variant expert-panel classification; its available Likely benign submissions are ordinary laboratory assertions and cannot trigger BP6.

N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · BP2 · BP3 · BP5 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.41623e-05; MAF= 0.00242%, 39/1614086 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20061e-05; MAF= 0.00320%, 2/62488 alleles, homozygotes = 0); grpmax FAF= 2.313e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.0606e-05; MAF= 0.00106%, 3/282860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.32259e-05; MAF= 0.00232%, 3/129166 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0024% · 39 / 1,614,086
0 hom · FAF 0.0023%

Remaining individuals 2 / 62,488	0.0032%
European (non-Finnish) 37 / 1,180,004	0.0031%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0011% · 3 / 282,860
0 hom · FAF 0.00029%

European (non-Finnish)

3 / 129,166

0.0023%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 52342)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.663. BayesDel score = 0.0999603.

SpliceAI ↗

Functional Likely Neutral

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

OncoKB ↗

COSMIC

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; COSV99061631, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.

PMID 29884841 ↗ · Hart SN et al. · 2019 Jan CLINVAR · functional

Searched

c.7484T>CNP_000050.3:p.(I2495T)

Found

The exact protein variant I2495T is shown among the 207 BRCA2 missense variants evaluated in the study's homology-directed repair assay dataset and displayed in Figure 1, but the extracted paper text does not provide a variant-specific HDR value or categorical result for I2495T.

Variant

✓ Names this variant — characterised directly

Applied to

→BS3 strong

I2495T Fig. 1 Homology-directed repair (HDR) activity of 207 BRCA2 missense variants.

Location Figure 1; Results, "Functional characterization of 68 novel BRCA2 missense variants" · Context Cell-based HDR assay in BRCA2-deficient V-C8 cells expressing mutant full-length BRCA2, using a DR-GFP reporter after induction of a DNA double-strand break; Figure 1 displays 207 BRCA2 missense variants. · full text

The functional impact of variants of uncertain significance in BRCA2.

PMID 29988080 ↗ · Mesman RLS et al. · 2019 Feb CLINVAR · functional

Searched

c.7484T>CNP_000050.3:p.(I2495T)

Found

The paper explicitly evaluated BRCA2 c.7484T>C, p.Ile2495Thr (NP_000050.3:p.(I2495T)) in an mESC-based functional assay. The variant complemented the lethal phenotype caused by loss of endogenous mouse Brca2, with HDR capacity of 58% relative to wild-type BRCA2 and cisplatin sensitivity of 84% of the wild-type control value.

Variant

✓ Names this variant — characterised directly

Applied to

→BS3 strong

Variant-specific calibrated mammalian functional results show complementation and near-neutral HDR and cisplatin responses rather than a damaging effect.

15 c.7484T>C p.Ile2495Thr Yes 58 84

Location Table 2, exon 15; HDR result also shown in Fig. 3b · Context Mouse embryonic stem cell assay measuring complementation after Cre-mediated loss of endogenous Brca2, HDR capacity using an I-Sce1-induced double-strand-break DR-GFP reporter, and cisplatin sensitivity relative to wild-type BRCA2-expressing cells. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

35736817 ↗ Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. ONCOKB

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

26689913 ↗ Patterns and functional implications of rare germline variants across 12 cancer types. CLINVAR

31131967 ↗ Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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