BRCA2c.8673_8674delPathogenic

Print report

Variant interpretation report

BRCA2 c.8673_8674del, p.(Arg2892ThrfsTer14)

NM_000059.4:c.8673_8674del NP_000050.3:p.(Arg2892ThrfsTer14) 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) · 3 supporting (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2.0
Other laboratories (ClinVar): 16 Pathogenic
Pipeline record: 16 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000059.4:c.8673_8674del is a 2-bp deletion in exon 21 causing a frameshift that produces p.Arg2892ThrfsTer14, a premature termination codon (PTC). Loss of function is an established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PVS1 at full (Very Strong) strength. The truncation removes 526 C-terminal amino acids including OB folds and nuclear localization signals within the DNA-binding domain (aa 2481-3186), and is predicted to trigger nonsense-mediated decay.
PM2 (supporting): This variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v4.1. Per ENIGMA PM2 rule, absence from population databases in an outbred population supports pathogenicity at Supporting strength.
PM5 (supporting): Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon. The variant c.8673_8674del creates a PTC (p.Arg2892ThrfsTer14) in exon 21, satisfying the PM5_PTC rule.
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 v1.2.0. 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: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PVS1Very strong

PVS1 · very strong

NM_000059.4:c.8673_8674del is a 2-bp deletion in exon 21 causing a frameshift that produces p.Arg2892ThrfsTer14, a premature termination codon (PTC). Loss of function is an established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PVS1 at full (Very Strong) strength. The truncation removes 526 C-terminal amino acids including OB folds and nuclear localization signals within the DNA-binding domain (aa 2481-3186), and is predicted to trigger nonsense-mediated decay.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v4.1. Per ENIGMA PM2 rule, absence from population databases in an outbred population supports pathogenicity at Supporting strength.

PM5Supporting

PM5 · supporting

Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon. The variant c.8673_8674del creates a PTC (p.Arg2892ThrfsTer14) in exon 21, satisfying the PM5_PTC rule.

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: Pathogenic

ENIGMA BRCA1/BRCA2 Specification Table 3 v1.2: 1 Very Strong criterion (PVS1) plus 3 Supporting criteria (PM2, PM5, PP5) satisfies the Pathogenic combination rule requiring ≥1 Very Strong + ≥2 Supporting. Confirmed by ENIGMA point system: PVS1(8) + PM2(1) + PM5(1) + PP5(1) = 11 points (≥10 = Pathogenic). No benign criteria are met.

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.

No listed criterion applied SpliceAI ↗

ClinVar submissions

16 reported laboratory submissions

16 Pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

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

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 v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 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

NM_000059.4:c.8673_8674del is a 2-bp frameshift deletion in BRCA2 exon 21 (DNA-binding domain, aa 2481-3186), producing a premature termination codon p.Arg2892ThrfsTer14. BRCA2 loss of function is a well-established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4 v1.2, PTC variants in exon 21 receive PVS1 at Very Strong strength.

The variant is absent from gnomAD v2.1 and v4.1 population databases, supporting pathogenicity (PM2 at Supporting strength per ENIGMA).

Per ENIGMA Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon.

ClinVar classifies this variant as Pathogenic with 3-star expert panel review by ENIGMA (Variation ID 52656). PP5 is met at Supporting strength.

Using the ENIGMA point system: PVS1 (Very Strong = 8) + PM2 (Supporting = 1) + PM5 (Supporting = 1) + PP5 (Supporting = 1) = 11 points. Score ≥10 meets the ENIGMA Pathogenic threshold. This also satisfies the ENIGMA Table 3 rule requiring 1 Very Strong criterion plus at least 2 Supporting criteria for Pathogenic classification.

Met · 4

PVS1 Very strongNM_000059.4:c.8673_8674del is a 2-bp deletion in exon 21 causing a frameshift that produces p.Arg2892ThrfsTer14, a premature termination codon (PTC). Loss of function is an established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PVS1 at full (Very Strong) strength. The truncation removes 526 C-terminal amino acids including OB folds and nuclear localization signals within the DNA-binding domain (aa 2481-3186), and is predicted to trigger nonsense-mediated decay. Details ▾Hide ▴

Evidence considered

Frameshift deletion in exon 21 creates PTC p.Arg2892ThrfsTer14 within DNA-binding domain (aa 2481-3186)
ENIGMA Table 4 assigns PVS1 (full strength) to PTC variants in BRCA2 exon 21
BRCA2 LOF is a well-established disease mechanism per CSPEC

Sources

cspec ↗vcep_specifications_table4_v1_2_2024_11_18

PM2 SupportingThis variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v4.1. Per ENIGMA PM2 rule, absence from population databases in an outbred population supports pathogenicity at Supporting strength. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (non-cancer
exome only subset)
Absent from gnomAD v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PM5 SupportingPer ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon. The variant c.8673_8674del creates a PTC (p.Arg2892ThrfsTer14) in exon 21, satisfying the PM5_PTC rule. Details ▾Hide ▴

Evidence considered

ENIGMA Table 4 assigns PM5_Supporting (PTC) to PTC variants in BRCA2 exon 21
Exon 21 is listed as PM5_PTC applicable (not in PM5_N/A exons E6
E12
E27)

Sources

vcep_specifications_table4_v1_2_2024_11_18cspec ↗

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

Evidence considered

ClinVar Variation ID 52656: Pathogenic
reviewed by ENIGMA expert panel (3-star)
16 clinical laboratories concur with Pathogenic classification
ClinVar expert panel classification

Sources

clinvar ↗cspec ↗

Not met · 12 · evaluated, threshold not reached

PS3 No variant-specific functional study testing NM_000059.4:c.8673_8674del was identified in the literature. OncoKB annotates this variant as Likely Loss-of-function based on curated context, but no direct experimental assay of this exact variant was found. Reviewed full-text papers discuss BRCA2 function at the gene level only. The ENIGMA Table 9 functional assay calibration covers missense and synonymous variants, not frameshift variants. Details ▾Hide ▴

Evidence considered

OncoKB classifies as Likely Oncogenic/Likely Loss-of-function but provides no variant-specific experimental citations

Still missing

No direct functional assay testing this exact variant

Sources

oncokb ↗

PS4 No case-control study with odds ratio and p-value meeting ENIGMA thresholds (OR ≥4, p ≤0.05, lower CI excludes 2.0) was identified. While this variant is reported in ClinVar as Pathogenic by 16 clinical laboratories, no formal case-control study has been performed. Details ▾Hide ▴

Evidence considered

ClinVar reports variant as Pathogenic (16 clinical laboratories
Variation ID 52656) but this does not constitute a formal case-control study

Still missing

No case-control study with effect size estimates available

Sources

clinvar ↗

PP1 No co-segregation data available. ENIGMA PP1 requires quantitative co-segregation analysis with LR ≥2.08 for Supporting strength. Details ▾Hide ▴

Still missing

No co-segregation LR data available

PP3 ENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains (BayesDel ≥0.30) or for predicted splicing (SpliceAI ≥0.2). This is a frameshift variant; BayesDel and REVEL scores are not applicable (deletion, not SNV). SpliceAI max delta = 0.0. PP3 criteria not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0 — no splicing impact predicted
Frameshift variant not eligible for PP3 under ENIGMA rules (missense/in-frame only)

Sources

spliceai ↗cspec ↗

PP4 Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for this variant is LR = 1.07 (3 probands), which falls in the neutral zone (0.48 < LR < 2.08). Per ENIGMA, PP4 requires LR ≥2.08 for Supporting strength. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 1.07 (3 probands
Li et al. 2020) — neutral
below PP4 Supporting threshold of LR ≥2.08

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

BA1 Variant is absent from gnomAD. ENIGMA BA1 requires FAF > 0.1% (FAF > 0.001) in gnomAD non-founder populations. Not met as variant is absent. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Variant is absent from gnomAD. ENIGMA BS1 requires FAF > 0.01% (Strong) or FAF > 0.002% (Supporting). Not met as variant is absent from all populations. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No proband-level data available to assess absence of Fanconi Anemia phenotype. ENIGMA BS2 requires specific proband data with points assignment per Table 8. Details ▾Hide ▴

Still missing

No proband phenotype data for BS2 assessment

BS3 No variant-specific functional studies showing no damaging effect were identified. ENIGMA Table 9 covers calibrated functional assays for missense and synonymous variants; this frameshift variant is not covered. No benign functional evidence exists. Details ▾Hide ▴

Still missing

No functional assay data showing no damaging effect

BS4 No segregation data available. ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation (LR ≤0.48 for Supporting). Details ▾Hide ▴

Still missing

No co-segregation data available

BP4 ENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with no predicted impact on protein or splicing. This is a frameshift variant, not eligible for BP4 under ENIGMA rules. Additionally, SpliceAI max delta = 0.0 but the frameshift itself is predicted to be damaging. Details ▾Hide ▴

Evidence considered

Frameshift variant not eligible for BP4 under ENIGMA rules
SpliceAI predicts no splice impact (max delta = 0.0)

Sources

spliceai ↗cspec ↗

BP5 Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for this variant is LR = 1.07 (3 probands), in the neutral zone (>0.48 and <2.08). Per ENIGMA, BP5 requires LR ≤0.48 for Supporting strength. Details ▾Hide ▴

Evidence considered

Clinical-history LR = 1.07 (3 probands
Li et al. 2020) — neutral
above BP5 Supporting threshold of LR ≤0.48

Sources

vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

Identifiers

Gene: BRCA2
Transcript: NM_000059.4
Coding (HGVS c.): NM_000059.4:c.8673_8674del
Protein (HGVS p.): NP_000050.3:p.(Arg2892ThrfsTer14)
GRCh38: chr13:32376709 CAA>C
GRCh37: chr13:32950846 CAA>C
ClinVar: 52656

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

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.0 — no splicing impact predicted
Frameshift variant not eligible for PP3 under ENIGMA rules (missense/in-frame only)

Sources

spliceai ↗cspec ↗

Evidence considered

Frameshift variant not eligible for BP4 under ENIGMA rules
SpliceAI predicts no splice impact (max delta = 0.0)

Sources

spliceai ↗cspec ↗

Sources

cspec ↗

Statement

In silico

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

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.

Reports that truncated BRCA2 protein products are mislocalized to the cytoplasm. Studies C-terminal truncations using GFP constructs in cell lines. The variant NM_000059.4:c.8673_8674del (p.Arg2892ThrfsTer14) was not specifically studied.
Does not name this variant
PMID 10570174 ↗
Quoted passage
The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function.
BRCA2 is required for homology-directed repair of chromosomal breaks.

Demonstrates that BRCA2 is required for homology-directed repair of chromosomal breaks using I-SceI endonuclease assays in BRCA2-mutant cell lines. The variant NM_000059.4:c.8673_8674del was not studied.
Does not name this variant
PMID 11239455 ↗
Quoted passage
We conclude that BRCA2 is a positive regulator of homology-directed repair at the chromosomal level.
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.

Reports a novel BRCA2 frameshift mutation c.7525_7526insT (exon 15) in an Italian woman with familial breast cancer history. The variant NM_000059.4:c.8673_8674del was not studied or discussed.
Does not name this variant
PMID 20878484 ↗
Quoted passage
The direct sequencing disclosed, on exon 15, an insertion (7525_7526insT).
BRCA1 and BRCA2: different roles in a common pathway of genome protection.

Review article comparing BRCA1 and BRCA2 roles in genome protection pathways. Discusses the two proteins at the gene/pathway level. The specific variant NM_000059.4:c.8673_8674del is not mentioned.
Does not name this variant
PMID 22193408 ↗
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.

Comprehensive review of global BRCA1 and BRCA2 mutation spectrum in breast cancer. Focuses on founder mutations and population-specific variants. The variant NM_000059.4:c.8673_8674del is not specifically identified in this review.
Does not name this variant
PMID 24312913 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

WECARE study characterizing BRCA1/2 deleterious mutations and VUS in women with contralateral versus unilateral breast cancer. Reports 113 unique deleterious mutations including 73 frameshift variants. The specific variant NM_000059.4:c.8673_8674del is not individually identified in the provided abstract or full-text as separately discussed.
Does not name this variant
PMID 20104584 ↗
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.

ACMG/AMP standards and guidelines for interpreting sequence variants. Provides the general framework for variant classification including PVS1, PM2, and combining criteria. This is a methodology document that does not discuss specific variants.
Does not name this variant
PMID 25741868 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Describes a standardized DNA variant scoring system for pathogenicity assessment across 338 genes and 11,894 variants. A methodology paper that does not discuss the specific variant NM_000059.4:c.8673_8674del.
Does not name this variant
PMID 26467025 ↗

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 16 Pathogenic 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (16 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52656)

In silico

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

Functional

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

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.