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BRCA2c.632-3C>GUncertain significance
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Variant interpretation report

BRCA2 c.632-3C>G, p.?

NM_000059.4:c.632-3C>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.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

This intronic variant is outside the canonical ±1,2 splice positions, but RNA studies identified complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele. Under the ENIGMA BRCA2 splicing framework, mRNA-only evidence for a noncanonical splice variant with apparent near-complete aberrant splicing supports PVS1 at RNA-adjusted strength rather than PS3.

PP5Supporting
PP5 · supporting

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework override from CSPEC/final_classification_framework was applied.

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
4 / 1,590,500 alleles

gnomAD v4.1: 4 / 1,590,500 alleles. Recorded AF 2.51493e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.11282e-06; MAF= 0.00041%, 1/243142 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.67913e-05; MAF= 0.00668%, 1/14972 alleles, homozygotes = 0).

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
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
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 11 not met · 6 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The BRCA2 c.632-3C>G (NP_000050.3:p.?) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.

This variant is rare in population databases, with 1/243142 alleles in gnomAD v2.1 (AF 0.00041%) and 4/1590500 alleles in gnomAD v4.1 (AF 0.00025%), which is below ENIGMA BA1 and BS1 thresholds but does not meet the absence requirement for PM2.

RNA splicing studies reported complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele, which is consistent with an RNA-based loss-of-function effect and supports PVS1_Strong (RNA) under the ENIGMA BRCA2 framework.

In silico splicing prediction also supports a spliceogenic effect, with SpliceAI max delta score 0.95, well above the ENIGMA PP3 splice threshold of 0.2, although PP3 is not scored separately when PVS1 is met.

Met · 2

PVS1 StrongThis intronic variant is outside the canonical ±1,2 splice positions, but RNA studies identified complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele. Under the ENIGMA BRCA2 splicing framework, mRNA-only evidence for a noncanonical splice variant with apparent near-complete aberrant splicing supports PVS1 at RNA-adjusted strength rather than PS3. Details ▾Hide ▴
Rule
PVS1_Strong (RNA)
Evidence considered
  • Splicing assay result: complete effect
  • Allele-specific assay reported
  • No wild-type transcript reported
  • Noncanonical splice-region variant with experimentally demonstrated loss of normal splicing
Still missing
  • The exact proportion of functional transcript retained was not reported as a quantitative percentage
  • so final RNA code weighting should be confirmed during expert review.
Sources
vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:22505045 ↗PMID:31131967 ↗
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar expert panel classification
Sources
vcep_specifications_v1_2_2024_11_18clinvar ↗

Not met · 11 · evaluated, threshold not reached

PS3 Available functional evidence is an mRNA splicing assay rather than a protein function assay. Under the ENIGMA BRCA2 specification, damaging mRNA-only evidence is captured under PVS1 (RNA) rather than PS3. Details ▾Hide ▴
Rule
mRNA-only damaging evidence maps to PVS1(RNA), not PS3
Evidence considered
  • mRNA splicing assay only
  • No variant-specific protein functional assay identified
Still missing
  • No calibrated protein-function assay result for this specific variant was identified.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:22505045 ↗
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/243142 alleles (AF 0.00041%) and in gnomAD v4.1 at 4/1590500 alleles (AF 0.00025%), so the ENIGMA PM2_Supporting absence requirement is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD controls
Evidence considered
  • gnomAD v2.1 AF 4.112822959422889e-06
  • gnomAD v4.1 AF 2.514932411191449e-06
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
PP3 SpliceAI predicts a strong splice effect for this variant (max delta score 0.95, above the PP3 threshold of 0.2), but the ENIGMA BRCA2 specification states that PP3 should not be applied when PVS1 is met at any strength. Predictive evidence is therefore noted but not scored separately. Details ▾Hide ▴
Rule
Do not apply PP3 if PVS1 is met at any strength
Evidence considered
  • SpliceAI max delta 0.95
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
PP4 Clinical-history likelihood data do not reach the ENIGMA PP4 threshold. The variant-specific BRCA2 clinical-history LR is 1.63 from 3 probands, which is below the supporting threshold of 2.08. Details ▾Hide ▴
Rule
PP4 requires LR >= 2.08
Evidence considered
  • Clinical-history LR 1.631523241892902
  • N probands 3
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18
BA1 Population frequency does not meet the ENIGMA BA1 threshold. The gnomAD v4.1 filter allele frequency is 0.00001752, which is below the BA1 threshold of 0.001, and the observed allele counts are low. Details ▾Hide ▴
Rule
BA1 requires FAF > 0.001
Evidence considered
  • gnomAD v4.1 grpmax FAF 1.752e-05
Sources
gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS1 Population frequency does not meet the ENIGMA BS1 threshold. The highest available filter allele frequency is 0.00001752 in gnomAD v4.1, which is below the supporting threshold of 0.00002 and well below the strong threshold of 0.0001. Details ▾Hide ▴
Rule
BS1_Supporting requires FAF > 0.00002; BS1 requires FAF > 0.0001
Evidence considered
  • gnomAD v4.1 grpmax FAF 1.752e-05
Still missing
  • gnomAD v2.1 filter allele frequency was not populated
  • but observed counts remain far below BS1 thresholds.
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS3 No benign protein-function evidence was identified for this variant. The available assay evidence shows splice disruption and is captured under PVS1 (RNA), not BS3. Details ▾Hide ▴
Rule
BS3 applies to protein-function evidence or mRNA no-damage evidence under BP7(RNA) context
Evidence considered
  • RNA assay showed complete splice effect
Still missing
  • No calibrated protein-function assay showing no damaging effect was identified.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:22505045 ↗
BP1 This criterion is not met because the variant is intronic and predicted to alter splicing. BP1 in BRCA2 is reserved for silent, missense, or in-frame variants outside critical domains with no predicted splice impact. Details ▾Hide ▴
Rule
BP1 requires no predicted splice impact
Evidence considered
  • Intronic variant
  • SpliceAI max delta 0.95
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 This criterion is not met because computational evidence predicts splice disruption. SpliceAI is 0.95, which is above the BP4 no-splicing-impact threshold of 0.1. Details ▾Hide ▴
Rule
BP4 requires SpliceAI <= 0.1
Evidence considered
  • SpliceAI max delta 0.95
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
BP5 Clinical-history likelihood data do not meet ENIGMA BP5 thresholds. The variant-specific BRCA2 clinical-history LR is 1.63, which is above the BP5 supporting threshold of 0.48 and therefore does not support a benign clinical-history code. Details ▾Hide ▴
Rule
BP5 requires LR <= 0.48
Evidence considered
  • Clinical-history LR 1.631523241892902
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18
BP7 This criterion is not met because the variant is at position c.632-3, which is not outside the low-conservation intronic region used for BP7 in BRCA2, and both prediction and RNA evidence show splice disruption rather than no impact. SpliceAI is 0.95, far above the BP7/BP4 no-impact threshold of 0.1. Details ▾Hide ▴
Rule
BP7 for intronic variants requires location at or beyond +7/-21 with no predicted or observed splice impact
Evidence considered
  • Position c.632-3 within near-splice region
  • SpliceAI max delta 0.95
  • RNA assay showed complete splice effect
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:22505045 ↗

Not assessed · 6 · no assessment recorded

PS1 No directly matched pathogenic or likely pathogenic reference variant with the same predicted splicing event was identified from the reviewed evidence, so PS1 was not assessed. Details ▾Hide ▴
Rule
PS1 splice comparator required
Evidence considered
  • ENIGMA splice-specific PS1 requires a known pathogenic or likely pathogenic comparator with the same predicted event
Still missing
  • A dedicated same-splicing-event comparison using the ENIGMA PS1 splice table was not available in the reviewed materials.
Sources
vcep_specifications_v1_2_2024_11_18
PS4 No qualifying case-control odds ratio or proband-counting evidence meeting ENIGMA PS4 requirements was identified for this variant. Multifactorial observations were reviewed, but those data are not sufficient on their own to assign PS4 here. Details ▾Hide ▴
Rule
PS4 requires qualifying case-control or approved proband-count evidence
Evidence considered
  • Multifactorial dataset reviewed
  • No direct PS4-eligible case-control result identified
Still missing
  • No variant-specific case-control analysis with p-value and odds ratio meeting ENIGMA PS4 thresholds was identified.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:31131967 ↗
PM3 No evidence was identified for this variant occurring with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 requires BRCA2-related Fanconi anemia context
Still missing
  • No biallelic Fanconi anemia case data were identified.
Sources
vcep_specifications_v1_2_2024_11_18
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative segregation evidence
Still missing
  • No pedigree-based likelihood ratio meeting ENIGMA PP1 thresholds was identified.
Sources
vcep_specifications_v1_2_2024_11_18
BS2 No evidence was identified showing this variant in trans with another BRCA2 variant in individuals lacking Fanconi anemia features, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 requires scored biallelic observations without Fanconi anemia phenotype
Still missing
  • No biallelic observation data relevant to BS2 were identified.
Sources
vcep_specifications_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative non-segregation evidence
Still missing
  • No pedigree-based LR meeting ENIGMA BS4 thresholds was identified.
Sources
vcep_specifications_v1_2_2024_11_18
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ANo de novo data were identified, and this criterion is not used in the BRCA2 ENIGMA specification for this evidence set. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
PM1 N/AThis is an intronic splice-region variant, and PM1 is not applicable in the BRCA2 ENIGMA specification for this type of evidence. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
PM4 N/APM4 is not applicable under the BRCA2 ENIGMA specification for this variant context. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
PM5 N/AThis variant is not a protein-terminating variant and no applicable PM5 comparator evidence was identified, so PM5 was not applied. Details ▾Hide ▴
Rule
PM5_PTC applies to protein-terminating variants in eligible exons
Evidence considered
  • Variant is a noncanonical intronic splice-region substitution
Sources
vcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM6 N/ANo assumed de novo evidence was identified, and this criterion is not used in the BRCA2 ENIGMA specification for this evidence set. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
PP2 N/APP2 is not applicable under the BRCA2 ENIGMA specification. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
BP2 N/ABP2 is not applicable under the BRCA2 ENIGMA specification. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
BP3 N/ABP3 is not applicable under the BRCA2 ENIGMA specification. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18
BP6 N/ABP6 is not applicable under the BRCA2 ENIGMA specification. Details ▾Hide ▴
Sources
vcep_specifications_v1_2_2024_11_18

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.632-3C>G
Protein (HGVS p.)
NP_000050.3:p.?
GRCh38
chr13:32329440 C>G
GRCh37
chr13:32903577 C>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…
gnomAD v4.1 4 / 1,590,500 alleles AF 2.51e-06 · 0 homozygotes · FAF 1.75e-05
gnomAD v2.1 1 / 243,142 alleles AF 4.11e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,590,500 alleles · 0 hom · FAF 1.8e-05
African/African American4 / 74,542 5.4e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

gnomAD v2.1

AF 4.1e-06 · 1 / 243,142 alleles · 0 hom
African/African American1 / 14,972 6.7e-05
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.51493e-06; MAF= 0.00025%, 4/1590500 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.3661e-05; MAF= 0.00537%, 4/74542 alleles, homozygotes = 0); grpmax FAF= 1.752e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.11282e-06; MAF= 0.00041%, 1/243142 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.67913e-05; MAF= 0.00668%, 1/14972 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts a strong splice effect for this variant (max delta score 0.95, above the PP3 threshold of 0.2), but the ENIGMA BRCA2 specification states that PP3 should not be applied when PVS1 is met at any strength. Predictive evidence is therefore noted but not scored separately. Details ▾Hide ▴
Rule
Do not apply PP3 if PVS1 is met at any strength
Evidence considered
  • SpliceAI max delta 0.95
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 This criterion is not met because computational evidence predicts splice disruption. SpliceAI is 0.95, which is above the BP4 no-splicing-impact threshold of 0.1. Details ▾Hide ▴
Rule
BP4 requires SpliceAI <= 0.1
Evidence considered
  • SpliceAI max delta 0.95
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
BP7 This criterion is not met because the variant is at position c.632-3, which is not outside the low-conservation intronic region used for BP7 in BRCA2, and both prediction and RNA evidence show splice disruption rather than no impact. SpliceAI is 0.95, far above the BP7/BP4 no-impact threshold of 0.1. Details ▾Hide ▴
Rule
BP7 for intronic variants requires location at or beyond +7/-21 with no predicted or observed splice impact
Evidence considered
  • Position c.632-3 within near-splice region
  • SpliceAI max delta 0.95
  • RNA assay showed complete splice effect
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:22505045 ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).

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 4 / 1,590,500 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record 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

This variant is present in gnomAD v4.1 (AF= 2.51493e-06; MAF= 0.00025%, 4/1590500 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.3661e-05; MAF= 0.00537%, 4/74542 alleles, homozygotes = 0); grpmax FAF= 1.752e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.11282e-06; MAF= 0.00041%, 1/243142 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.67913e-05; MAF= 0.00668%, 1/14972 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (5 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as likely pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).

Somatic

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