BRCA2c.29_63delPathogenic

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Variant interpretation report

BRCA2 c.29_63del, p.(Thr10SerfsTer9)

NM_000059.4:c.29_63del NP_000050.3:p.(Thr10SerfsTer9) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

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: 1 very strong (pathogenic) · 1 strong (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This variant is a 35 bp deletion in BRCA2 exon 2 that causes a frameshift and premature termination, p.(Thr10SerfsTer9). Loss of function is an established disease mechanism for BRCA2, and ENIGMA BRCA2 Table 4 assigns exon 2 protein-truncating variants PVS1; this supports PVS1 at very strong strength.
PM5 (strong): This variant creates a premature termination codon in BRCA2 exon 2. ENIGMA BRCA2 Table 4 assigns PM5_Strong (PTC) to exon 2 protein-truncating variants when PVS1 is applicable, so this criterion is met at strong strength.

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

PVS1Very strong

PVS1 · very strong

This variant is a 35 bp deletion in BRCA2 exon 2 that causes a frameshift and premature termination, p.(Thr10SerfsTer9). Loss of function is an established disease mechanism for BRCA2, and ENIGMA BRCA2 Table 4 assigns exon 2 protein-truncating variants PVS1; this supports PVS1 at very strong strength.

PM5Strong

PM5 · strong

This variant creates a premature termination codon in BRCA2 exon 2. ENIGMA BRCA2 Table 4 assigns PM5_Strong (PTC) to exon 2 protein-truncating variants when PVS1 is applicable, so this criterion is met at strong strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework (official CSPEC/VCEP final-classification framework).

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.

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

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

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 · 2 not met · 11 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The BRCA2 c.29_63del (p.(Thr10SerfsTer9)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar; OncoKB classifies p.(T10Sfs*9) as Likely Oncogenic with a likely loss-of-function effect.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0 in the queried population datasets.

The deletion causes an early frameshift with premature termination in exon 2, and ENIGMA BRCA2 Table 4 assigns exon 2 protein-truncating variants PVS1 and PM5_Strong (PTC), which supports a loss-of-function disease mechanism for this variant.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.04.

Met · 2

PVS1 Very strongThis variant is a 35 bp deletion in BRCA2 exon 2 that causes a frameshift and premature termination, p.(Thr10SerfsTer9). Loss of function is an established disease mechanism for BRCA2, and ENIGMA BRCA2 Table 4 assigns exon 2 protein-truncating variants PVS1; this supports PVS1 at very strong strength. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PVS1 for exon 2 protein-truncating variants

Evidence considered

NM_000059.4:c.29_63del is predicted as NP_000050.3:p.(Thr10SerfsTer9)
VariantValidator places the deletion in exon 2
ENIGMA Table 4 marks BRCA2 exon 2 PTC variants as PVS1
BRCA2 loss of function is established as a disease mechanism in the applied VCEP framework

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8

PM5 StrongThis variant creates a premature termination codon in BRCA2 exon 2. ENIGMA BRCA2 Table 4 assigns PM5_Strong (PTC) to exon 2 protein-truncating variants when PVS1 is applicable, so this criterion is met at strong strength. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM5_Strong for exon 2 PTC variants

Evidence considered

Variant is a frameshift with premature termination
Variant is located in exon 2
ENIGMA Table 4 marks BRCA2 exon 2 PTC variants as PM5_Strong (PTC)

Sources

cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8

Not met · 2 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0 and is below the ENIGMA BA1 threshold of greater than 0.1% (FAF > 0.001). BA1 is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BA1

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0 and is below the ENIGMA BS1 thresholds of greater than 0.01% for BS1 or greater than 0.002% for BS1_Supporting. BS1 is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BS1

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS1 No evidence was identified showing that this variant produces the same amino acid change or the same predicted splice effect as a previously classified pathogenic or likely pathogenic BRCA2 variant. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PS1

Evidence considered

Variant is a frameshift deletion with predicted premature termination

Still missing

No qualifying pathogenic reference variant with the same protein or splice consequence was identified.

Sources

cspec ↗

PS3 No variant-specific calibrated functional study result was identified for NM_000059.4:c.29_63del in the curated ENIGMA functional table, so PS3 cannot be applied from the available evidence. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PS3

Evidence considered

No match for c.29_63del or p.(Thr10SerfsTer9) was identified in ENIGMA Table 9

Still missing

No variant-specific calibrated protein or combined mRNA/protein assay result was identified.

Sources

cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗

PS4 No case-control study or quantitative enrichment data were identified showing that this variant is significantly more frequent in affected individuals than in controls, so PS4 is not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PS4

Evidence considered

Variant is absent from ClinVar
Variant was not found in COSMIC
No qualifying ENIGMA case-control evidence for this variant was identified

Still missing

No qualifying case-control odds ratio or p-value was identified.

Sources

cspec ↗clinvar ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8

PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0 in the queried datasets. However, the ENIGMA PM2 rule specifies absence in gnomAD v2.1 and v3.1 with adequate read depth, and the required v3.1 and coverage confirmation were not identified here, so PM2 was not adjudicated as met. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM2_Supporting

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1

Still missing

No gnomAD v3.1 confirmation was identified.
No region-level read-depth confirmation meeting the ENIGMA requirement was identified.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 is not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM3

Evidence considered

No biallelic BRCA2 Fanconi anemia evidence was provided

Still missing

No qualifying Fanconi anemia phenotype or trans configuration evidence was identified.

Sources

cspec ↗

PP1 No segregation data were identified for this variant, so co-segregation evidence supporting pathogenicity was not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PP1

Evidence considered

No segregation evidence was provided

Still missing

No family-based segregation likelihood ratio was identified.

Sources

cspec ↗

PP4 No multifactorial likelihood analysis or other quantitative phenotype-specific evidence was identified for this variant, so PP4 was not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PP4

Evidence considered

No variant-specific multifactorial likelihood evidence was identified

Still missing

No qualifying multifactorial likelihood ratio was identified.

Sources

cspec ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1

BS2 No evidence was identified showing this variant in individuals lacking features of BRCA2-related Fanconi anemia under the ENIGMA BS2 framework, so BS2 was not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BS2

Evidence considered

No BS2-qualifying clinical observations were provided

Still missing

No qualifying point-based BS2 evidence was identified.

Sources

cspec ↗

BS3 No variant-specific calibrated functional study showing no damaging effect was identified for NM_000059.4:c.29_63del, so BS3 cannot be applied from the available evidence. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BS3

Evidence considered

No match for c.29_63del or p.(Thr10SerfsTer9) was identified in ENIGMA Table 9

Still missing

No variant-specific benign functional assay result was identified.

Sources

cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗

BS4 No lack-of-segregation data were identified for this variant, so BS4 was not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BS4

Evidence considered

No family-based non-segregation evidence was identified

Still missing

No quantitative segregation likelihood ratio against pathogenicity was identified.

Sources

cspec ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1

BP5 No multifactorial likelihood evidence arguing against pathogenicity was identified for this variant, so BP5 was not established. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP5

Evidence considered

No BP5-qualifying multifactorial data were identified

Still missing

No qualifying multifactorial likelihood ratio against pathogenicity was identified.

Sources

cspec ↗

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS2 N/ADe novo evidence is not used for BRCA2 in the applied ENIGMA specification, so this criterion is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PS2 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PS2 as not applicable

Sources

cspec ↗

PM1 N/APM1 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM1 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PM1 as not applicable

Sources

cspec ↗

PM4 N/APM4 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM4 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PM4 as not applicable

Sources

cspec ↗

PM6 N/AAssumed de novo evidence is not used for BRCA2 in the applied ENIGMA specification, so this criterion is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PM6 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PM6 as not applicable

Sources

cspec ↗

PP2 N/APP2 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PP2 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PP2 as not applicable

Sources

cspec ↗

PP3 N/APP3 in the BRCA2 ENIGMA specification is used for missense, in-frame, silent, or relevant intronic variants with predicted splice or protein impact. This variant is a frameshift deletion, so PP3 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PP3 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

PP5 N/APP5 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 PP5 not applicable

Evidence considered

ENIGMA BRCA2 specification lists PP5 as not applicable

Sources

cspec ↗

BP1 N/ABP1 in the BRCA2 ENIGMA specification applies to silent, missense, or in-frame variants outside clinically important domains without predicted splice impact. This variant is a frameshift deletion, so BP1 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP1 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

BP2 N/ABP2 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP2 not applicable

Evidence considered

ENIGMA BRCA2 specification lists BP2 as not applicable

Sources

cspec ↗

BP3 N/ABP3 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP3 not applicable

Evidence considered

ENIGMA BRCA2 specification lists BP3 as not applicable

Sources

cspec ↗

BP4 N/ABP4 in the BRCA2 ENIGMA specification applies to selected missense, in-frame, silent, or intronic variants with no predicted impact. This variant is a frameshift deletion, so BP4 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP4 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

BP6 N/ABP6 is not applicable in the BRCA2 ENIGMA specification for this interpretation framework. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP6 not applicable

Evidence considered

ENIGMA BRCA2 specification lists BP6 as not applicable

Sources

cspec ↗

BP7 N/ABP7 in the BRCA2 ENIGMA specification applies to silent, intronic, or selected RNA-tested variants without damaging splice effect. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA2 v1.2 BP7 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

Identifiers

Gene: BRCA2
Transcript: NM_000059.4
Coding (HGVS c.): NM_000059.4:c.29_63del
Protein (HGVS p.): NP_000050.3:p.(Thr10SerfsTer9)
GRCh38: chr13:32316486 CAACATTTTTTGAAATTTTTAAGACACGCTGCAACA>C
GRCh37: chr13:32890623 CAACATTTTTTGAAATTTTTAAGACACGCTGCAACA>C

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

—

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

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

ENIGMA BRCA2 v1.2 PP3 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

Rule

ENIGMA BRCA2 v1.2 BP4 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

Rule

ENIGMA BRCA2 v1.2 BP7 scope excludes this variant class

Evidence considered

Variant class is frameshift
SpliceAI max delta score is 0.04

Sources

cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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 Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB 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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.