BRCA2c.5238dupNot classified

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Variant interpretation report

BRCA2 c.5238dup, p.(Asn1747Ter)

NM_000059.4:c.5238dup NP_000050.3:p.(Asn1747Ter) View identifiers

Classification

Not classified

Variant description:

No variant summary was recorded for this case.

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

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About BRCA2

No gene-level summary was recorded for this case.

Key facts

Condition: BRCA2-related cancer predisposition
Inheritance: Autosomal dominant
Evidence used: 1 very strong (pathogenic) · 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2
Other laboratories (ClinVar): 39 Pathogenic · 1 pathogenic · 1 not provided
Pipeline record: 31 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): BRCA2 c.5238dupT is a frameshift variant in exon 11 resulting in a premature termination codon at p.Asn1747Ter. Loss of function is an established disease mechanism for BRCA2. Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC is located well upstream of the last exon (exon 27). The variant is absent from gnomAD v2.1.
PM5 (strong): Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 qualify for PM5_Strong (PTC). Exon 11 is not a PM5_N/A exon (PM5_N/A exons for BRCA2: E6, E12, E27 only). A PTC in exon 11 where other proven pathogenic PTC variants have been observed supports this additional weight.
PP5 (supporting): Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

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. 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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

BRCA2 c.5238dupT is a frameshift variant in exon 11 resulting in a premature termination codon at p.Asn1747Ter. Loss of function is an established disease mechanism for BRCA2. Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC is located well upstream of the last exon (exon 27). The variant is absent from gnomAD v2.1.

PM5Strong

PM5 · strong

Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 qualify for PM5_Strong (PTC). Exon 11 is not a PM5_N/A exon (PM5_N/A exons for BRCA2: E6, E12, E27 only). A PTC in exon 11 where other proven pathogenic PTC variants have been observed supports this additional weight.

PP5Supporting

PP5 · supporting

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Not classified

No source classification-combination explanation was recorded.

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

3 / 1,610,822 alleles

gnomAD v4.1: 3 / 1,610,822 alleles. Recorded AF 1.8624e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied

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.

No listed criterion applied SpliceAI ↗

ClinVar submissions

41 reported laboratory submissions

39 Pathogenic · 1 pathogenic · 1 not provided. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

In progress — evidence not uploaded yet.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

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

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, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 9 not met · 0 not assessed · 17 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 PS5

Benign

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

Met Not met Not assessed Not applicable

BRCA2 NM_000059.4:c.5238dupT (p.Asn1747Ter) is a frameshift variant in exon 11 resulting in a premature termination codon at position 1747. Loss of function is an established disease mechanism for BRCA2.

Per ENIGMA BRCA2 Specifications Table 4 (v1.2, 2024-11-18), PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC occurs well upstream of the final exon.

Per ENIGMA BRCA2 Specifications Table 4, exon 11 PTC variants also qualify for PM5_Strong (PTC), as exon 11 is not among the PM5_N/A exons (E6, E12, E27). Multiple proven pathogenic PTC variants have been observed in this exon.

In ClinVar (Variation ID 37954), this variant is classified as Pathogenic with review status 'reviewed by expert panel' (ENIGMA), supported by 39 clinical laboratory submissions. PP5 is applied at supporting strength per the ClinVar 3-star expert panel override.

The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.86e-06, 3/1,610,822 alleles, grpmax FAF=6.8e-07). Clinical-history likelihood ratio is neutral (LR=1.717).

Classification: Pathogenic. PVS1 (Very Strong) + PM5_Strong (PTC) satisfies ENIGMA Table 3 pathogenic combination rules (1 Very Strong + 1 Strong = Pathogenic).

Met · 3

PVS1 Very strongBRCA2 c.5238dupT is a frameshift variant in exon 11 resulting in a premature termination codon at p.Asn1747Ter. Loss of function is an established disease mechanism for BRCA2. Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC is located well upstream of the last exon (exon 27). The variant is absent from gnomAD v2.1. Details ▾Hide ▴

Evidence considered

ENIGMA Table 4: BRCA2 exon 11 PTC → PVS1 (Very Strong)
NMD predicted — PTC at codon 1747 in 48.1% exon 11
far from last exon
BRCA2 LOF is established germline disease mechanism per ClinGen ENIGMA specifications

Sources

vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextgnomad_v2 ↗PMID:25682074 ↗

PM5 StrongPer ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 qualify for PM5_Strong (PTC). Exon 11 is not a PM5_N/A exon (PM5_N/A exons for BRCA2: E6, E12, E27 only). A PTC in exon 11 where other proven pathogenic PTC variants have been observed supports this additional weight. Details ▾Hide ▴

Evidence considered

ENIGMA Table 4: BRCA2 exon 11 PTC → PM5_Strong (PTC)

Sources

vcep_specifications_table4_v1_2_2024_11_18

PP5 SupportingExpert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 37954: Pathogenic
reviewed by expert panel (ENIGMA)
39 clinical laboratories classify as Pathogenic
PP5 override applied: ClinVar 3-star EP → Supporting strength
ClinVar expert panel classification

Sources

clinvar ↗

Not met · 9 · evaluated, threshold not reached

PS4 No case-control study with p≤0.05 and OR≥4 is available for this variant. The variant has been observed in affected individuals (PMID:25682074 reports c.5237dup p.Asn1747* in a TNBC cohort), but no formal case-control statistical comparison has been performed per ENIGMA PS4 requirements. Details ▾Hide ▴

Evidence considered

Variant observed in TNBC cohort (Wong-Brown et al. 2015) but no case-control OR available

Still missing

No case-control study with formal OR/p-value available

Sources

PMID:25682074 ↗

PM2 The ENIGMA BRCA2 PM2 rule requires absence from gnomAD v2.1 (non-cancer, exome) AND v3.1 (non-cancer). The variant is absent from v2.1 but is present in gnomAD v4.1 at extremely low frequency (AF=1.86e-06; 3/1,610,822 alleles; highest in European non-Finnish, 3/1,177,880). Under strict CSPEC rules requiring absence from both v2.1 and v3.1, the presence in the successor v4.1 dataset precludes PM2_Supporting. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1
Present in gnomAD v4.1 at AF=1.86e-06 (3 alleles)
grpmax FAF=6.8e-07

Still missing

CSPEC rule references v3.1
not v4.1
v3.1 data not explicitly available

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP1 No co-segregation data or quantitative segregation likelihood ratio is available for this variant. Per ENIGMA PP1 rules, a Bayes Score LR≥2.08 is required for Supporting strength. No such data has been provided. Details ▾Hide ▴

Still missing

No co-segregation analysis available

PP4 Per PMID:31853058 clinical-history likelihood ratio table, BRCA2 c.5238dupT has LR=1.717 (LOG(LR)=0.540, N_Probands=10). This falls within the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 is applicable. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 1.717 (10 probands) — neutral zone
no PP4/BP5

Sources

vcep_pmid_31853058_brca2_clinical_history_lr

BA1 BA1 requires FAF > 0.1% (FAF > 0.001) in gnomAD v2.1/v3.1 non-cancer. The variant is absent from v2.1 and has grpmax FAF = 6.8e-07 (0.000068%) in v4.1, far below the BA1 threshold. Details ▾Hide ▴

Evidence considered

FAF = 6.8e-07 — far below 0.1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 BS1 requires FAF > 0.01% (Strong) or >0.002% (Supporting). The variant has grpmax FAF = 6.8e-07 (0.000068%), which is far below the BS1_Supporting threshold of 0.002%. Absent from gnomAD v2.1. BS1 is not met. Details ▾Hide ▴

Evidence considered

FAF = 6.8e-07 — far below BS1_Supporting threshold of 0.002%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 BS2 requires documented absence of Fanconi Anemia phenotype features with sufficient proband points per ENIGMA Table 8. No proband-level phenotype data is available in the case materials to assess BS2. Details ▾Hide ▴

Still missing

No proband phenotype data available for BS2 assessment

BS4 BS4 requires lack of segregation in affected family members, quantified by LR≤0.05 (Strong) or LR≤0.48 (Supporting). No segregation data is available for this variant. Details ▾Hide ▴

Still missing

No segregation data available

BP5 Per PMID:31853058 clinical-history LR table, BRCA2 c.5238dupT has LR=1.717 which falls in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 applies. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 1.717 — neutral zone

Sources

vcep_pmid_31853058_brca2_clinical_history_lr

Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense substitutions or exonic/intronic variants with same predicted splicing impact as a previously classified pathogenic variant. This is a frameshift/duplication variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PS2 VCEPPS2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

PS3 N/AENIGMA Table 9 (PS3/BS3 functional assays) does not list this variant. Table 9 is calibrated for missense, synonymous, and selected splice-site variants. The variant is a frameshift/PTC; functional assay calibration is not applicable for null/frameshift variants in the ENIGMA framework as the PVS1+PM5 combination already captures the null effect. Details ▾Hide ▴

Evidence considered

Not listed in ENIGMA Table 9 BRCA2 PS3/BS3 functional assay catalog

Sources

vcep_specifications_table9_v1_2_2024_11_18

PM1 VCEPPM1 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

PM3 N/APM3 is skipped per user directive — trivially not applicable for this case. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

PM6 VCEPPM6 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPPP2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

PP3 N/AENIGMA PP3 applies to missense/in-frame variants inside a functional domain with BayesDel≥0.30, or variants with SpliceAI≥0.2. This is a frameshift/PTC variant. BayesDel and REVEL are not applicable (not an SNV). SpliceAI max delta score is 0.00, indicating no predicted splicing impact. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splicing impact)
Variant is frameshift
not missense/in-frame — PP3 rules do not apply

Sources

spliceai ↗

BS3 N/AENIGMA Table 9 (BS3 functional assays) does not list this variant. BS3 in the ENIGMA framework applies to missense/synonymous variants with calibrated functional studies showing no damaging effect. The variant is a frameshift/PTC, and its null effect is already captured by PVS1+PM5. Details ▾Hide ▴

Evidence considered

Not listed in ENIGMA Table 9 BRCA2 BS3 functional assay catalog

Sources

vcep_specifications_table9_v1_2_2024_11_18

BP1 N/AENIGMA BP1 applies to silent substitutions, missense, or in-frame insertion/deletion variants outside a clinically important functional domain with no splicing predicted. This is a frameshift/PTC variant; BP1 does not apply. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPBP2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPBP3 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. Details ▾Hide ▴

Sources

cspec ↗

BP4 N/AENIGMA BP4 applies to missense/in-frame variants inside a functional domain with no predicted protein or splicing impact, or silent/intronic variants with no splicing impact. This is a frameshift/PTC variant; BP4 rules do not apply. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. ClinVar classification is Pathogenic (expert panel reviewed), so the PP5/BP6 override would apply PP5 at supporting rather than BP6. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/AENIGMA BP7 applies to silent variants inside a clinically important functional domain, or intronic variants outside conserved splice motifs, when BP4 is met. This is a frameshift/PTC variant; BP7 rules do not apply. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not part of the ENIGMA BRCA1/BRCA2 VCEP framework. This criterion is not assessed under the active specification. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: BRCA2
Transcript: NM_000059.4
Coding (HGVS c.): NM_000059.4:c.5238dup
Protein (HGVS p.): NP_000050.3:p.(Asn1747Ter)
GRCh38: chr13:32339592 C>CT
GRCh37: chr13:32913729 C>CT
ClinVar: 37954, 495468

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 3 / 1,610,822 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,610,822 alleles · 0 hom · FAF 6.8e-07

European (non-Finnish)3 / 1,177,880

2.5e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.8624e-06; MAF= 0.00019%, 3/1610822 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54695e-06; MAF= 0.00025%, 3/1177880 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -215 bp

0.000

SpliceAI acceptor gainat +7 bp

0.000

SpliceAI donor lossat +28 bp

0.000

SpliceAI donor gainat -107 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

SpliceAI max delta = 0.00 (no splicing impact)
Variant is frameshift
not missense/in-frame — PP3 rules do not apply

Sources

spliceai ↗

No further detail was recorded.

Statement

In silico

In progress — evidence not uploaded yet.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

No paper-specific finding is recorded.

PMID 10570174 ↗
BRCA2 is required for homology-directed repair of chromosomal breaks.

No paper-specific finding is recorded.

PMID 11239455 ↗
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.

No paper-specific finding is recorded.

PMID 20878484 ↗
BRCA1 and BRCA2: different roles in a common pathway of genome protection.

No paper-specific finding is recorded.

PMID 22193408 ↗
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.

No paper-specific finding is recorded.

PMID 24312913 ↗
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.

No paper-specific finding is recorded.

PMID 11802209 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A et al. · 2010

No paper-specific finding is recorded.

PMID 20104584 ↗
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.

Wong-Brown MW et al. · 2015

No paper-specific finding is recorded.

PMID 25682074 ↗

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

gnomAD v4.1 3 / 1,610,822 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 39 Pathogenic · 1 pathogenic · 1 not provided 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

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

In progress — evidence not uploaded yet.

In silico

In progress — evidence not uploaded yet.

Functional

In progress — evidence not uploaded yet.

Somatic

In progress — evidence not uploaded yet.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Literature

In progress — evidence not uploaded yet.