BRCA2c.8633-24T>GUncertain significance

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Variant interpretation report

BRCA2 c.8633-24T>G, p.?

NM_000059.4:c.8633-24T>G NP_000050.3:p.? View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BRCA2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2.0
Pipeline record: 19 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): NM_000059.4:c.8633-24T>G is absent from gnomAD v2.1 (exomes, non-cancer) and gnomAD v4.1 (genomes, non-cancer) across all populations. Per ENIGMA BRCA2 VCEP v1.2.0, PM2 is applied at Supporting strength when a variant is absent from controls in outbred populations. Read depth at this intronic position should be confirmed as ≥25x per VCEP requirements.
BP4 (supporting): c.8633-24T>G is an intronic variant located outside the native donor and acceptor splice sites (position -24, beyond +/-1,2) with no predicted impact on splicing (SpliceAI max delta score 0.00, ≤0.1). BP4 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0.
BP7 (supporting): c.8633-24T>G is located at intron 20 position -24, which is beyond the conserved acceptor splice motif (beyond -21). BP4 is met (SpliceAI max delta 0.00). BP7 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0, which applies to intronic variants outside conserved donor/acceptor motif positions when BP4 criteria are satisfied.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen BRCA2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

NM_000059.4:c.8633-24T>G is absent from gnomAD v2.1 (exomes, non-cancer) and gnomAD v4.1 (genomes, non-cancer) across all populations. Per ENIGMA BRCA2 VCEP v1.2.0, PM2 is applied at Supporting strength when a variant is absent from controls in outbred populations. Read depth at this intronic position should be confirmed as ≥25x per VCEP requirements.

Benign criteria applied · 2

BP4Supporting

BP4 · supporting

c.8633-24T>G is an intronic variant located outside the native donor and acceptor splice sites (position -24, beyond +/-1,2) with no predicted impact on splicing (SpliceAI max delta score 0.00, ≤0.1). BP4 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0.

BP7Supporting

BP7 · supporting

c.8633-24T>G is located at intron 20 position -24, which is beyond the conserved acceptor splice motif (beyond -21). BP4 is met (SpliceAI max delta 0.00). BP7 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0, which applies to intronic variants outside conserved donor/acceptor motif positions when BP4 criteria are satisfied.

Recorded classification: Uncertain significance

ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3 conflicting evidence point system: PM2 (Supporting, +1) vs BP4 (Supporting Benign, -1) + BP7 (Supporting Benign, -1). Total score = -1, which falls in the 'Uncertain Significance' range (-1 to 5). Both pathogenic and benign criteria are met, so the point system takes precedence over the non-conflicting likely_benign rule (2 Supporting Benign).

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 5 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000059.4:c.8633-24T>G is an intronic variant in BRCA2 located at position -24 of intron 20. This variant is absent from gnomAD v2.1 (exomes) and v4.1 (genomes) across all populations, meeting PM2 at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0 (pending read depth confirmation at this intronic position).

SpliceAI predicts no splicing impact (max delta score 0.00). Combined with its location outside the canonical +/-1,2 splice consensus and beyond the conserved acceptor motif (position -24, beyond -21), this meets BP4_Supporting and BP7_Supporting per ENIGMA BRCA2 VCEP v1.2.0.

The variant is not present in ClinVar and has not been reported in the published literature. No functional assay data, case-control studies, segregation data, or clinical-history likelihood ratios are available for this specific variant.

Per ENIGMA BRCA1 and BRCA2 VCEP Table 3 combining rules, two Supporting Benign criteria (BP4 + BP7) meet the threshold for Likely Benign. The classification is provisional pending confirmation of gnomAD read depth at position c.8633-24.

Met · 3

PM2 SupportingNM_000059.4:c.8633-24T>G is absent from gnomAD v2.1 (exomes, non-cancer) and gnomAD v4.1 (genomes, non-cancer) across all populations. Per ENIGMA BRCA2 VCEP v1.2.0, PM2 is applied at Supporting strength when a variant is absent from controls in outbred populations. Read depth at this intronic position should be confirmed as ≥25x per VCEP requirements. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes
non-cancer
all populations)
Absent from gnomAD v4.1 (genomes
Absent from gnomAD-Canada v1.0

Still missing

Confirm read depth ≥25x at c.8633-24 in gnomAD v2.1 exomes
deep intronic positions may have reduced exome capture coverage

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

BP4 Supportingc.8633-24T>G is an intronic variant located outside the native donor and acceptor splice sites (position -24, beyond +/-1,2) with no predicted impact on splicing (SpliceAI max delta score 0.00, ≤0.1). BP4 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

Intronic variant at position -24
outside canonical +/-1
2 splice sites
SpliceAI max delta score 0.00
no predicted splicing impact

Sources

spliceai ↗cspec ↗

BP7 Supportingc.8633-24T>G is located at intron 20 position -24, which is beyond the conserved acceptor splice motif (beyond -21). BP4 is met (SpliceAI max delta 0.00). BP7 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0, which applies to intronic variants outside conserved donor/acceptor motif positions when BP4 criteria are satisfied. Details ▾Hide ▴

Evidence considered

Position -24 is beyond the conserved acceptor splice motif (beyond -21)
BP4 is met
satisfying the prerequisite for BP7_Supporting
SpliceAI max delta score 0.00

Sources

spliceai ↗cspec ↗

Not met · 5 · evaluated, threshold not reached

PVS1 c.8633-24T>G is an intronic variant at position -24 of intron 20, outside the canonical donor/acceptor +/-1,2 splice consensus. It is not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion) and no RNA functional studies demonstrating a damaging effect on mRNA transcript profile are available. PVS1 is not met per ENIGMA BRCA2 VCEP v1.2.0 rules. Details ▾Hide ▴

Evidence considered

Intronic substitution at position -24
not at canonical +/-1
2 splice site
SpliceAI max delta score 0.00
no predicted splicing impact
No RNA/mRNA functional assay data available

Sources

cspec ↗pvs1_generic_framework ↗

PS1 No previously classified pathogenic variant at the same nucleotide position with the same predicted splicing effect is available for comparison. SpliceAI predicts no splicing impact (max delta 0.00), and there is no comparator variant to support PS1 per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

No pathogenic comparator variant identified at c.8633-24
SpliceAI max delta 0.00 indicates no predicted splicing impact

Sources

cspec ↗spliceai ↗

PP3 SpliceAI predicts no significant splicing impact (max delta score 0.00, below the ≥0.2 threshold). The variant is intronic and BayesDel/REVEL are not applicable (no protein change). PP3 is not met per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.00
below PP3 threshold of ≥0.2
No protein-level in silico scores available (intronic variant)

Sources

spliceai ↗cspec ↗

BA1 The variant is absent from gnomAD v2.1 and v4.1 across all populations. Filter allele frequency does not exceed 0.1% (FAF > 0.001). BA1 is not met per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD v2.1 and v4.1
FAF does not exceed BA1 threshold of 0.1%

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 The variant is absent from gnomAD v2.1 and v4.1 across all populations. Filter allele frequency does not exceed the BS1_Strong threshold of 0.01% (FAF > 0.0001) or the BS1_Supporting threshold of 0.002% (FAF > 0.00002). BS1 is not met per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

Variant absent from gnomAD v2.1 and v4.1
FAF does not exceed BS1 thresholds

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS3 No functional assay data available for NM_000059.4:c.8633-24T>G. The variant is not listed in ENIGMA Table 9 (curated BRCA2 functional assay results) and no published functional studies were identified. Details ▾Hide ▴

Evidence considered

Variant absent from ENIGMA Table 9 functional assay dataset
No published functional studies identified in literature pass

Still missing

No functional assay data available for this variant

Sources

vcep_specifications_table9_v1_2_2024_11_18

PS4 No case-control study data available for this variant. The variant is absent from ClinVar and gnomAD, precluding prevalence comparison between affected individuals and controls. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
Variant absent from gnomAD v2.1 and v4.1

Still missing

No case-control or cohort enrichment data available

Sources

clinvar ↗gnomad_v2 ↗gnomad_v4 ↗

PP1 No co-segregation data available for this variant. No family studies or likelihood ratio analyses for co-segregation were identified. Details ▾Hide ▴

Still missing

No co-segregation or family segregation data available

PP4 The variant NM_000059.4:c.8633-24T>G is not present in the ENIGMA clinical-history likelihood ratio dataset (PMID:31853058, Li et al. 2020). No combined LR from multifactorial clinical data is available to support PP4. Details ▾Hide ▴

Evidence considered

Variant not listed in Li et al. 2020 clinical-history LR table

Still missing

No clinical-history likelihood ratio data available for this variant

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

BS2 No proband data available to assess absence of Fanconi Anemia phenotype features. BS2 per ENIGMA BRCA2 VCEP v1.2.0 requires point-based assessment of co-occurrence with a second pathogenic variant in the absence of recessive disease features. Details ▾Hide ▴

Still missing

No proband data available for BS2 points assessment

Sources

cspec ↗

BS3 No functional assay data showing no damaging effect is available for this variant. The variant is not listed in ENIGMA Table 9 (curated BRCA2 functional assay results). Details ▾Hide ▴

Evidence considered

Variant absent from ENIGMA Table 9 functional assay dataset

Still missing

No functional assay data available showing no damaging effect

Sources

vcep_specifications_table9_v1_2_2024_11_18

BS4 No co-segregation data available to assess lack of segregation in affected family members. BS4 requires quantitative co-segregation analysis per ENIGMA BRCA2 VCEP v1.2.0. Details ▾Hide ▴

Still missing

No co-segregation or family segregation data available

Sources

cspec ↗

BP5 The variant NM_000059.4:c.8633-24T>G is not present in the ENIGMA clinical-history likelihood ratio dataset (PMID:31853058, Li et al. 2020). No combined LR against pathogenicity from multifactorial clinical data is available to support BP5. Details ▾Hide ▴

Evidence considered

Variant not listed in Li et al. 2020 clinical-history LR table

Still missing

No clinical-history likelihood ratio data available for this variant

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PS2 VCEPPS2 is not applicable per ENIGMA BRCA2 VCEP v1.2.0 specifications. Details ▾Hide ▴

Sources

cspec ↗

PM1 VCEPPM1 is not applicable per ENIGMA BRCA2 VCEP v1.2.0; mutational hotspot and functional domain evidence is folded into bioinformatic analysis under PP3/BP4. Details ▾Hide ▴

Sources

cspec ↗

PM5 N/APM5 is repurposed for PTC/truncating variant logic per ENIGMA BRCA2 VCEP v1.2.0 (PM5_PTC). c.8633-24T>G is an intronic substitution, not a protein termination codon variant. PM5_PTC does not apply. Details ▾Hide ▴

Evidence considered

Intronic substitution
not a PTC variant
PM5_PTC logic requires a nonsense
frameshift
or canonical splice variant leading to premature termination

Sources

cspec ↗vcep_specifications_table4_v1_2_2024_11_18

PM6 VCEPPM6 is not applicable per ENIGMA BRCA2 VCEP v1.2.0 specifications. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPPP2 is not applicable per ENIGMA BRCA2 VCEP v1.2.0 specifications. Details ▾Hide ▴

Sources

cspec ↗

PP5 VCEPPP5 is not applicable per ENIGMA BRCA2 VCEP v1.2.0; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Sources

cspec ↗

BP1 N/ABP1 per ENIGMA BRCA2 VCEP v1.2.0 applies only to silent substitutions, missense variants, or in-frame insertions/deletions/delins outside clinically important functional domains. c.8633-24T>G is an intronic substitution and does not fall within the specified variant types for BP1. Details ▾Hide ▴

Evidence considered

Intronic substitution
not a silent/missense/in-frame variant covered by BP1

Sources

cspec ↗

BP2 VCEPBP2 is not applicable per ENIGMA BRCA2 VCEP v1.2.0 specifications. Details ▾Hide ▴

Sources

cspec ↗

BP6 VCEPBP6 is not applicable per ENIGMA BRCA2 VCEP v1.2.0 specifications. Details ▾Hide ▴

Sources

cspec ↗

PS5 N/APS5 is not part of the ENIGMA BRCA2 VCEP v1.2.0 specification. Details ▾Hide ▴

Sources

cspec ↗

Identifiers

Gene: BRCA2
Transcript: NM_000059.4
Coding (HGVS c.): NM_000059.4:c.8633-24T>G
Protein (HGVS p.): NP_000050.3:p.?
GRCh38: chr13:32376646 T>G
GRCh37: chr13:32950783 T>G

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.

BRCA2NM_000059.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in BRCA2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +24 bp

0.000

SpliceAI acceptor gainat +71 bp

0.000

SpliceAI donor lossat +191 bp

0.000

SpliceAI donor gainat +311 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

Intronic variant at position -24
outside canonical +/-1
2 splice sites
SpliceAI max delta score 0.00
no predicted splicing impact

Sources

spliceai ↗cspec ↗

Evidence considered

Position -24 is beyond the conserved acceptor splice motif (beyond -21)
BP4 is met
satisfying the prerequisite for BP7_Supporting
SpliceAI max delta score 0.00

Sources

spliceai ↗cspec ↗

Evidence considered

SpliceAI max delta score 0.00
below PP3 threshold of ≥0.2
No protein-level in silico scores available (intronic variant)

Sources

spliceai ↗cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).