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BRCA1c.2182A>TPathogenic
Print report
Variant interpretation report

BRCA1 c.2182A>T, p.(Arg728Ter)

NM_007294.4:c.2182A>T NP_009225.1:p.(Arg728Ter) 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 BRCA1

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 BRCA1 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Nonsense variant NM_007294.4:c.2182A>T (p.Arg728Ter) in BRCA1 exon 10 (legacy exon 11). BRCA1 loss of function is an established disease mechanism. The PTC occurs at codon 728 within the large exon 10 (c.671-4096, codons 224-1366), located >1900 nt upstream of the exon 10-11 junction, predicting nonsense-mediated decay. Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 at full (Very Strong) weight.

PM2Supporting
PM2 · supporting

Absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA specification, absence from outbred population controls in gnomAD qualifies for PM2_Supporting.

PM5Strong
PM5 · strong

ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10 (legacy exon 11). This exon has multiple proven pathogenic PTC variants, and the PM5_PTC code is supported by sufficient evidence across functional assay, case-control, personal/family history, and CIMBA data per Supplementary Table 1.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ENIGMA BRCA1/2 VCEP point system (Table 3): PVS1 Very Strong (8 points) + PM5 Strong (4 points) + PM2 Supporting (1 point) = 13 points, exceeding the Pathogenic threshold (≥10). Also satisfies the categorical rule: 1 Very Strong (PVS1) + ≥1 Strong (PM5) → Pathogenic.

02The sources

Evidence at a glance

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

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
2 reported laboratory submissions

2 Pathogenic.

Context only 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 BRCA1 VCEP v1.2.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 7 not met · 1 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_007294.4:c.2182A>T (p.Arg728Ter) is a nonsense variant in BRCA1 exon 10 (legacy exon 11), predicted to undergo nonsense-mediated decay (>1900 nt upstream of the terminal exon junction).

Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 (Very Strong) weight. Loss of function is an established disease mechanism for BRCA1.

ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10, where multiple proven pathogenic PTC variants have been observed. This is supported by ≥4 evidence points across functional assay, case-control, personal/family history, and CIMBA data (Supplementary Table 1).

The variant is absent from gnomAD v2.1 (non-cancer, exome only), gnomAD v4.1 (non-cancer), and gnomAD-Canada v1.0, meeting ENIGMA PM2_Supporting.

ENIGMA point-based combining rules (Table 3): PVS1 Very Strong (8 points) + PM5 Strong (4 points) + PM2 Supporting (1 point) = 13 points, meeting the Pathogenic threshold (≥10 points).

Met · 3

PVS1 Very strongNonsense variant NM_007294.4:c.2182A>T (p.Arg728Ter) in BRCA1 exon 10 (legacy exon 11). BRCA1 loss of function is an established disease mechanism. The PTC occurs at codon 728 within the large exon 10 (c.671-4096, codons 224-1366), located >1900 nt upstream of the exon 10-11 junction, predicting nonsense-mediated decay. Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 at full (Very Strong) weight. Details ▾Hide ▴
Evidence considered
  • ENIGMA Table 4: BRCA1 exon 10 (legacy E11) PTC → PVS1
  • Nonsense variant p.Arg728Ter in exon 10
  • NMD predicted (>1900 nt upstream of terminal junction)
  • BRCA1 LOF established disease mechanism per CSPEC
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
PM2 SupportingAbsent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA specification, absence from outbred population controls in gnomAD qualifies for PM2_Supporting. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗
PM5 StrongENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10 (legacy exon 11). This exon has multiple proven pathogenic PTC variants, and the PM5_PTC code is supported by sufficient evidence across functional assay, case-control, personal/family history, and CIMBA data per Supplementary Table 1. Details ▾Hide ▴
Evidence considered
  • ENIGMA Table 4: BRCA1 exon 10 PTC → PM5_Strong (PTC)
  • ENIGMA ST1: BRCA1 exon 10 PM5_PTC code = Strong
  • ≥4 points across evidence types
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18

Not met · 7 · evaluated, threshold not reached

PS4 ENIGMA PS4 requires a case-control study with p-value ≤ 0.05 and OR ≥ 4 (lower CI excludes 2.0). No published case-control study for this specific variant is available. The variant has been observed in affected individuals through clinical testing and is absent from gnomAD, but these observations do not meet the formal PS4 threshold. Details ▾Hide ▴
Evidence considered
  • ClinVar: 2 clinical laboratories classify as Pathogenic
  • gnomAD: absent from v2.1
  • v4.1
  • and Canada
Still missing
  • No published case-control study with OR ≥ 4 for this specific variant
  • ClinVar case observations not formally quantified per ENIGMA PS4 requirements
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PP1 ENIGMA PP1 requires quantitative co-segregation analysis yielding an LR ≥ 2.08 (Supporting). No co-segregation likelihood ratio data for this variant was available in the case materials. The variant was not listed in the clinical-history LR spreadsheet (PMID:31853058). Details ▾Hide ▴
Still missing
  • No co-segregation LR data available for this variant
  • Variant absent from the clinical-history LR spreadsheet (Li et al. 2020)
PP4 ENIGMA PP4 requires a clinical-history likelihood ratio ≥ 2.08 (Supporting) from multifactorial likelihood clinical data. The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history LR spreadsheet. No other clinical-history LR data is available. Details ▾Hide ▴
Evidence considered
  • Li et al. 2020 clinical-history LR spreadsheet: variant not listed
Still missing
  • Variant absent from BRCA1 clinical-history LR table
  • No multifactorial likelihood data available
Sources
vcep_pmid_31853058_brca1_clinical_history_lr
BA1 ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 non-cancer exome or v3.1 non-cancer, non-founder populations. The variant is absent from all gnomAD populations. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: FAF not computed (absent)
  • gnomAD v4.1: FAF not computed (absent)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 ENIGMA BS1 requires FAF > 0.01% (Strong) or FAF > 0.002% and ≤ 0.01% (Supporting) in gnomAD non-cancer subsets. The variant is absent from all gnomAD populations. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS4 ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation in affected family members (LR ≤ 0.48 for Supporting). No BS4-applicable co-segregation data is available for this variant. Details ▾Hide ▴
Still missing
  • No co-segregation data available to assess BS4
BP5 ENIGMA BP5 requires a clinical-history LR ≤ 0.48 (Supporting) from multifactorial likelihood data. The variant was not found in the Li et al. 2020 clinical-history LR spreadsheet. No data supports BP5. Details ▾Hide ▴
Still missing
  • Variant absent from clinical-history LR table

Not assessed · 1 · no assessment recorded

BS2 ENIGMA BS2 requires absence of Fanconi Anemia phenotype features and ≥ 4 points under the Specification Table 8 scoring system. No systematic FA phenotype screening data for carriers of this specific variant is available for review. Details ▾Hide ▴
Still missing
  • No systematic Fanconi Anemia phenotype data available for this variant
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense substitutions or splicing variants with a previously classified pathogenic comparator. This is a nonsense (PTC) variant; PS1 is not applicable per ENIGMA specification. Details ▾Hide ▴
Sources
cspec ↗
PS2 VCEPPS2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
PS3 N/APS3/BS3 functional assay codes in ENIGMA Specification Table 9 apply to missense and synonymous variants. This is a nonsense (PTC) variant; the functional consequence (truncation/NMD) is captured by PVS1. PS3 is not applicable. Details ▾Hide ▴
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PM1 VCEPPM1 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
PM3 N/APM3 per ENIGMA requires Fanconi Anemia phenotype with co-occurrent variants in trans and specific scoring under Specification Table 6. No FA case data with this variant is available for review in the case materials. Details ▾Hide ▴
Still missing
  • Exploratory search identified PMID:25480564 as potentially containing FA case with c.2182A>T in trans
  • full text not available for verification
PM4 VCEPPM4 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification (not applicable to BRCA1/2). Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPPP2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
PP3 N/AENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≥ 0.28, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). This is a nonsense variant with SpliceAI max delta 0.00 and BayesDel 0.18. PP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.00
  • BayesDel no-AF score: 0.18
Sources
cspec ↗spliceai ↗bayesdel
PP5 VCEPPP5 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
BS3 N/AENIGMA BS3 functional assay codes (Specification Table 9) apply to missense and synonymous variants. This is a nonsense variant; the functional consequence is captured by PVS1. Details ▾Hide ▴
Sources
cspec ↗
BP1 N/AENIGMA BP1_Strong applies to silent, missense, or in-frame variants outside clinically important functional domains with SpliceAI ≤ 0.1. This is a nonsense (PTC) variant; BP1 is not applicable. Details ▾Hide ▴
Sources
cspec ↗
BP2 VCEPBP2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPBP3 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification (captured by bioinformatic tool prediction and domain analysis). Details ▾Hide ▴

No further detail was recorded.

BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. This is a nonsense variant; BP4 is not applicable. BayesDel score is 0.18 (>0.15 threshold). Details ▾Hide ▴
Evidence considered
  • BayesDel no-AF score: 0.18 (> 0.15 BP4 threshold)
Sources
cspec ↗bayesdel
BP6 VCEPBP6 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/AENIGMA BP7 applies to intronic and silent variants, and to missense/in-frame variants outside clinically important functional domains when mRNA assay shows no damaging effect. This is a nonsense (PTC) variant; BP7 is not applicable. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/APS5 is not included in the ENIGMA BRCA1/2 VCEP criteria set. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.2182A>T
Protein (HGVS p.)
NP_009225.1:p.(Arg728Ter)
GRCh38
chr17:43093349 T>A
GRCh37
chr17:41245366 T>A
ClinVar
2811747, 868990, 409352, 89056, 54647

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.

BRCA1NM_007294.4
Fetching transcript structure from UCSC…
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 +7 bp
0.000
SpliceAI acceptor gainat -445 bp
0.000
SpliceAI donor lossat -221 bp
0.000
SpliceAI donor gainat -29 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.180

How the predictions were used

PP3 N/AENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≥ 0.28, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). This is a nonsense variant with SpliceAI max delta 0.00 and BayesDel 0.18. PP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.00
  • BayesDel no-AF score: 0.18
Sources
cspec ↗spliceai ↗bayesdel
BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. This is a nonsense variant; BP4 is not applicable. BayesDel score is 0.18 (>0.15 threshold). Details ▾Hide ▴
Evidence considered
  • BayesDel no-AF score: 0.18 (> 0.15 BP4 threshold)
Sources
cspec ↗bayesdel
BP7 N/AENIGMA BP7 applies to intronic and silent variants, and to missense/in-frame variants outside clinically important functional domains when mRNA assay shows no damaging effect. This is a nonsense (PTC) variant; BP7 is not applicable. Details ▾Hide ▴
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.179714.

9 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

  • Tumorigenesis in mice carrying a truncating Brca1 mutation.
    No paper-specific finding is recorded.
    PMID 11358863 ↗
  • The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.
    No paper-specific finding is recorded.
    PMID 12483515 ↗
  • Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
    No paper-specific finding is recorded.
    PMID 12947386 ↗
  • BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
    No paper-specific finding is recorded.
    PMID 20608970 ↗
  • 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 ↗
  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    No paper-specific finding is recorded.
    PMID 12692171 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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 2 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 (2 clinical laboratories). (ClinVarID = 2811747)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.179714.

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.