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BRCA2c.8362T>CLikely pathogenic
Print report
Variant interpretation report

BRCA2 c.8362T>C, p.(Trp2788Arg)

NM_000059.3:c.8362T>C NP_000050.2:p.(Trp2788Arg) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely 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.

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
PS3Strong
PS3 · strong

In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 protein function. The BRCA2 VCEP Table 9 assigns PS3 at Strong strength for c.8362T>C (p.Trp2788Arg).

PM2Supporting
PM2 · supporting

This variant was absent from gnomAD v2.1 and absent from gnomAD v4.1 in the reviewed population data, which is consistent with rarity in population controls and supports PM2 at Supporting strength.

PP3Supporting
PP3 · supporting

This missense variant is located in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.314871, which is above the BRCA2 PP3 threshold of 0.30 for a damaging protein effect. REVEL is also high at 0.897. SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, so the computational evidence supports a protein-level damaging interpretation rather than a splicing effect.

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: Likely pathogenic

Official ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules)

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

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

Applied · PP3 →
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.

Applied · PS3 → 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: 4 met · 8 not met · 5 not assessed · 11 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.8362T>C (p.Trp2788Arg, p.W2788R) variant has not been observed in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert panel classification from ClinGen ENIGMA.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting PM2 at Supporting strength.

In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, and the BRCA2 VCEP functional evidence table assigns PS3 at Strong strength, supporting a damaging effect on BRCA2 function.

Computational evidence supports a damaging protein effect: the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314871, REVEL is 0.897, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

Met · 4

PS3 StrongIn a calibrated functional study, this variant showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 protein function. The BRCA2 VCEP Table 9 assigns PS3 at Strong strength for c.8362T>C (p.Trp2788Arg). Details ▾Hide ▴
Rule
BRCA2 VCEP Table 9 curated functional-assay assignment.
Evidence considered
  • Table 9 entry: BRCA2 c.8362T>C p.(Trp2788Arg) PS3 Strong
  • Richardson 2021 functional result reported as damaging
Sources
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗vcep_specifications_v1_2_2024_11_18
PM2 SupportingThis variant was absent from gnomAD v2.1 and absent from gnomAD v4.1 in the reviewed population data, which is consistent with rarity in population controls and supports PM2 at Supporting strength. Details ▾Hide ▴
Rule
BRCA2 VCEP applies PM2 at Supporting strength for absence from controls.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
PP3 SupportingThis missense variant is located in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.314871, which is above the BRCA2 PP3 threshold of 0.30 for a damaging protein effect. REVEL is also high at 0.897. SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, so the computational evidence supports a protein-level damaging interpretation rather than a splicing effect. Details ▾Hide ▴
Rule
BRCA2 PP3 applies for missense variants in a clinically important domain with BayesDel no-AF >= 0.30.
Evidence considered
  • BayesDel no-AF 0.314871
  • REVEL 0.897
  • SpliceAI max delta 0.03
  • Variant lies in BRCA2 DNA-binding domain
Sources
bayesdelrevelspliceai ↗vcep_specifications_v1_2_2024_11_18
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Evidence considered
  • PP5 listed as not applicable in BRCA2 VCEP rules
  • ClinVar expert panel classification
Sources
vcep_specifications_v1_2_2024_11_18clinvar ↗

Not met · 8 · evaluated, threshold not reached

PS4 No qualifying case-control enrichment data were identified. In the reviewed BRCA2 multifactorial dataset, this variant had a combined likelihood ratio of 1.02 and was specifically noted as not meeting the thresholds for supportive pathogenic or benign multifactorial evidence, so PS4 is not met. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals under BRCA2 VCEP rules.
Evidence considered
  • Parsons supplementary dataset combined LR 1.0246153856
  • Dataset note: combined LR is not <0.5 or >2
Still missing
  • Independent case-control data with odds ratio and confidence interval were not identified.
Sources
vcep_humu_40_1557_s001vcep_specifications_v1_2_2024_11_18
PP4 In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband. That value is below the PP4 Supporting threshold of 2.08, so PP4 is not met. Details ▾Hide ▴
Rule
BRCA2 PP4 requires LR >= 2.08.
Evidence considered
  • Clinical-history LR 1.222259878837825
  • N probands 1
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18
BA1 This variant was absent from the reviewed gnomAD datasets and therefore is well below the BRCA2 BA1 threshold of filter allele frequency greater than 0.001. BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires filter allele frequency > 0.001.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS1 This variant was absent from the reviewed gnomAD datasets and therefore does not reach the BRCA2 BS1 thresholds of filter allele frequency greater than 0.00002 or greater than 0.0001. BS1 is not met. Details ▾Hide ▴
Rule
BS1 Supporting requires FAF > 0.00002 and Strong requires FAF > 0.0001.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 absent
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS3 Available calibrated functional evidence supports a damaging effect rather than normal function. The BRCA2 VCEP Table 9 assigns PS3 Strong for this variant, so BS3 is not met. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
  • Table 9 entry assigns PS3 Strong
  • Functional result reported as damaging
Sources
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗vcep_specifications_v1_2_2024_11_18
BP1 BP1_Strong for BRCA2 is limited to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This variant is within the BRCA2 DNA-binding domain, so BP1 is not met. Details ▾Hide ▴
Rule
BRCA2 BP1_Strong requires location outside the PALB2-binding and DNA-binding domains and no splice prediction.
Evidence considered
  • Variant located in BRCA2 DNA-binding domain
  • SpliceAI max delta 0.03
Sources
spliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 For a missense variant in a clinically important BRCA2 domain, BP4 requires BayesDel no-AF 0.18 or lower and SpliceAI 0.1 or lower. SpliceAI is low at 0.03, but BayesDel is 0.314871, which is above the benign threshold, so BP4 is not met. Details ▾Hide ▴
Rule
BRCA2 BP4 requires BayesDel no-AF <= 0.18 and SpliceAI <= 0.1 in qualifying contexts.
Evidence considered
  • BayesDel no-AF 0.314871
  • SpliceAI max delta 0.03
Sources
bayesdelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP5 In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband. That value is above the BP5 benign thresholds and falls in the neutral zone above 0.48 and below 2.08, so BP5 is not met. Details ▾Hide ▴
Rule
BRCA2 BP5 requires LR <= 0.48.
Evidence considered
  • Clinical-history LR 1.222259878837825
  • N probands 1
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18

Not assessed · 5 · no assessment recorded

PS1 PS1 requires a previously classified variant that produces the same amino acid change. No codon-level comparison evidence establishing that requirement was identified in the reviewed sources. Details ▾Hide ▴
Rule
Apply for the same amino acid change as a previously classified pathogenic or likely pathogenic variant under BRCA2 VCEP rules.
Evidence considered
  • PS1 rule reviewed
Still missing
  • Targeted codon-level search for another nucleotide change causing p.Trp2788Arg with an established pathogenic or likely pathogenic classification.
Sources
vcep_specifications_v1_2_2024_11_18
PM3 No evidence was identified for occurrence with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
BRCA2 PM3 is restricted to qualifying Fanconi anemia evidence.
Evidence considered
  • PM3 rule reviewed
Still missing
  • No phase data or 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
BRCA2 PP1 requires quantitative co-segregation evidence.
Evidence considered
  • PP1 rule reviewed
Still missing
  • Informative family segregation data with a quantitative likelihood ratio were not identified.
Sources
vcep_specifications_v1_2_2024_11_18
BS2 No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for points-based BS2 assessment, so BS2 was not assessed. Details ▾Hide ▴
Rule
BRCA2 BS2 uses a Fanconi-anemia points framework.
Evidence considered
  • BS2 rule reviewed
Still missing
  • No BS2 point-based clinical data were identified.
Sources
vcep_specifications_v1_2_2024_11_18
BS4 No quantitative non-segregation analysis with a likelihood ratio at or below the BRCA2 BS4 thresholds was identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
BRCA2 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
  • No qualifying BS4 likelihood-ratio evidence identified
Still missing
  • Informative family non-segregation data with quantitative likelihood-ratio analysis were not identified.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant, so the BRCA2 PVS1 framework does not apply. Details ▾Hide ▴
Rule
BRCA2 PVS1 is reserved for qualifying loss-of-function or RNA-null events.
Evidence considered
  • p.(Trp2788Arg) missense consequence
  • generic PVS1 scaffold marked this variant outside null-variant buckets
Sources
pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18
PS2 N/AThis BRCA2 VCEP framework does not use PS2 for this variant assessment context. Details ▾Hide ▴
Evidence considered
  • PS2 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
PM1 N/AAlthough codon 2788 lies within the BRCA2 DNA-binding region, PM1 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • PM1 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM4 N/APM4 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • PM4 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
PM5 N/AThe BRCA2 VCEP PM5 framework reviewed here is for protein-truncating variants in eligible exons. This variant is missense, so that PM5 framework does not apply. Details ▾Hide ▴
Evidence considered
  • PM5 rule in reviewed BRCA2 materials is PTC-specific
Sources
vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
PM6 N/AThis BRCA2 VCEP framework does not use PM6 for this variant assessment context. Details ▾Hide ▴
Evidence considered
  • PM6 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
PP2 N/APP2 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • PP2 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
BP2 N/ABP2 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • BP2 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
BP3 N/ABP3 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • BP3 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
BP6 N/ABP6 is designated as not applicable in this BRCA2 VCEP framework. Details ▾Hide ▴
Evidence considered
  • BP6 listed as not applicable in BRCA2 VCEP rules
Sources
vcep_specifications_v1_2_2024_11_18
BP7 N/ABP7 in this BRCA2 framework is used for silent or intronic variants, or for specific RNA-only evidence contexts. This is a missense variant in a clinically important domain, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence
  • Variant located in BRCA2 DNA-binding domain
Sources
vcep_specifications_v1_2_2024_11_18spliceai ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.3
Coding (HGVS c.)
NM_000059.3:c.8362T>C
Protein (HGVS p.)
NP_000050.2:p.(Trp2788Arg)
GRCh38
chr13:32370432 T>C
GRCh37
chr13:32944569 T>C

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.3. Select a row to find it on the plot.

BRCA2NM_000059.3
Fetching transcript structure from UCSC…
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

PP3 SupportingThis missense variant is located in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.314871, which is above the BRCA2 PP3 threshold of 0.30 for a damaging protein effect. REVEL is also high at 0.897. SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, so the computational evidence supports a protein-level damaging interpretation rather than a splicing effect. Details ▾Hide ▴
Rule
BRCA2 PP3 applies for missense variants in a clinically important domain with BayesDel no-AF >= 0.30.
Evidence considered
  • BayesDel no-AF 0.314871
  • REVEL 0.897
  • SpliceAI max delta 0.03
  • Variant lies in BRCA2 DNA-binding domain
Sources
bayesdelrevelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 For a missense variant in a clinically important BRCA2 domain, BP4 requires BayesDel no-AF 0.18 or lower and SpliceAI 0.1 or lower. SpliceAI is low at 0.03, but BayesDel is 0.314871, which is above the benign threshold, so BP4 is not met. Details ▾Hide ▴
Rule
BRCA2 BP4 requires BayesDel no-AF <= 0.18 and SpliceAI <= 0.1 in qualifying contexts.
Evidence considered
  • BayesDel no-AF 0.314871
  • SpliceAI max delta 0.03
Sources
bayesdelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP7 N/ABP7 in this BRCA2 framework is used for silent or intronic variants, or for specific RNA-only evidence contexts. This is a missense variant in a clinically important domain, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense consequence
  • Variant located in BRCA2 DNA-binding domain
Sources
vcep_specifications_v1_2_2024_11_18spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.897. BayesDel score = 0.314871.

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 has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.897. BayesDel score = 0.314871.

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.