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BRCA2c.7685T>GLikely pathogenic
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Variant interpretation report

BRCA2 c.7685T>G, p.(Phe2562Cys)

NM_000059.3:c.7685T>G NP_000050.2:p.(Phe2562Cys) 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 BRCA2 functional study summarized in the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, and the ENIGMA resource assigns PS3 at strong strength.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population controls and supports PM2 at supporting strength under the ENIGMA BRCA2 framework.

PP3Supporting
PP3 · supporting

This missense variant lies in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30. REVEL is also high at 0.921, while SpliceAI is low at 0.01, supporting a damaging protein effect rather than a splice effect; together these findings support PP3 at supporting strength.

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

ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 final-classification framework (CSPEC/VCEP override).

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 · 7 not met · 6 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.7685T>G (p.Phe2562Cys; p.F2562C) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.

In a calibrated BRCA2 functional study summarized by the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, supporting PS3_Strong.

This missense change lies in the BRCA2 DNA-binding domain; BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.921, and SpliceAI predicts little splice effect with a maximum delta score of 0.01.

In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 0.9916 in 1 proband, which is within the neutral zone and does not support PP4 or BP5.

Met · 4

PS3 StrongIn a calibrated BRCA2 functional study summarized in the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, and the ENIGMA resource assigns PS3 at strong strength. Details ▾Hide ▴
Evidence considered
  • ENIGMA Table 9 row for c.7685T>G
  • PS3 Strong assignment
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population controls and supports PM2 at supporting strength under the ENIGMA BRCA2 framework. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Still missing
  • The ENIGMA specification references gnomAD v3.1 depth-aware review
  • direct depth confirmation was not available here.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
PP3 SupportingThis missense variant lies in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30. REVEL is also high at 0.921, while SpliceAI is low at 0.01, supporting a damaging protein effect rather than a splice effect; together these findings support PP3 at supporting strength. Details ▾Hide ▴
Evidence considered
  • BRCA2 DNA-binding domain location
  • BayesDel no-AF 0.421539
  • REVEL 0.921
  • SpliceAI max delta 0.01
Sources
cspec ↗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
  • ENIGMA BRCA2 applicability listing
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 7 · evaluated, threshold not reached

PP4 In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband. This value is within the neutral zone between 0.48 and 2.08 and therefore does not support PP4. Details ▾Hide ▴
Evidence considered
  • Clinical-history LR 0.9915619280023366
  • N probands 1
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not approach the ENIGMA BRCA2 BA1 threshold of filter allele frequency greater than 0.001. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BRCA2 BS1 frequency threshold of filter allele frequency greater than 0.00002 for supporting or greater than 0.0001 for strong benign evidence. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
BS3 Available calibrated functional evidence does not show normal protein function. In the ENIGMA BRCA functional assay table, this variant is assigned PS3_Strong rather than BS3, so BS3 is not supported. Details ▾Hide ▴
Evidence considered
  • ENIGMA Table 9 assignment: PS3 Strong
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗
BP1 This missense variant is within the BRCA2 DNA-binding domain at residue 2562, and ENIGMA applies BP1_Strong only to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. Although SpliceAI is low at 0.01, the domain criterion for BP1 is not met. Details ▾Hide ▴
Evidence considered
  • Residue 2562 lies in BRCA2 DNA-binding domain
  • SpliceAI max delta 0.01
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 This missense variant is in the BRCA2 DNA-binding domain (amino acids 2481-3186), where ENIGMA applies BP4 only when BayesDel no-AF is less than or equal to 0.18 and SpliceAI is less than or equal to 0.1. SpliceAI is low at 0.01, but BayesDel is 0.421539, which is above the benign threshold and does not support BP4. Details ▾Hide ▴
Evidence considered
  • BRCA2 DNA-binding domain location
  • BayesDel no-AF 0.421539
  • SpliceAI max delta 0.01
Sources
cspec ↗bayesdelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP5 In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband. This value is above the BP5 supporting threshold of 0.48 and therefore does not support BP5. Details ▾Hide ▴
Evidence considered
  • Clinical-history LR 0.9915619280023366
  • N probands 1
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

Not assessed · 6 · no assessment recorded

PS1 No evidence was identified that a previously classified pathogenic or likely pathogenic variant causes the same amino acid change or the same splicing effect, so PS1 cannot be assessed from the available evidence. Details ▾Hide ▴
Evidence considered
  • No qualifying PS1 comparator identified
Still missing
  • A qualifying same-amino-acid or same-splicing comparator variant was not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 No case-control dataset or other quantitative evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No qualifying PS4 enrichment evidence identified
Still missing
  • A qualifying odds ratio and confidence interval
  • or other accepted ENIGMA PS4 evidence
  • were not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No qualifying PM3 data identified
Still missing
  • Confirmed trans observations and Fanconi anemia phenotype details were not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No segregation data were identified to show co-segregation of this variant with disease in affected relatives, so PP1 cannot be assessed from the available evidence. Details ▾Hide ▴
Evidence considered
  • No informative segregation evidence identified
Still missing
  • Family segregation data or a quantitative segregation likelihood ratio were not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No qualifying evidence was identified showing this variant in individuals without a Fanconi anemia phenotype under the ENIGMA BRCA2 BS2 scoring framework, so BS2 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No qualifying BS2 observations identified
Still missing
  • Point-based BS2 evidence from informative observations was not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No quantitative non-segregation data were identified to show lack of segregation with disease in affected relatives, so BS4 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No informative BS4 evidence identified
Still missing
  • A quantitative segregation likelihood ratio supporting non-segregation was not identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution rather than a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant. SpliceAI predicts no meaningful splice disruption with a maximum delta score of 0.01, so available evidence does not support applying PVS1. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • Generic PVS1 scaffold not applicable
  • SpliceAI max delta 0.01
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗vcep_specifications_v1_2_2024_11_18
PS2 N/APS2 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
PM1 N/APM1 is not applied in the ENIGMA BRCA2 specification for this gene framework, even for variants within important domains. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM4 N/APM4 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
PM5 N/AIn the ENIGMA BRCA2 framework, PM5 is repurposed for truncating or protein-termination variants rather than classic same-residue missense logic. Because this is a missense substitution, PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • PM5 mode is PTC-specific for BRCA2
  • Classic same-residue PM5 search not eligible
Sources
cspec ↗pm5_candidatesvcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
PP2 N/APP2 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
BP2 N/ABP2 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
BP3 N/ABP3 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
BP6 N/ABP6 is not applicable in the ENIGMA BRCA2 specification for this gene framework. Details ▾Hide ▴
Evidence considered
  • ENIGMA BRCA2 applicability listing
Sources
cspec ↗
BP7 N/ABP7 is intended for synonymous or certain intronic variants without splice impact and is not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • SpliceAI max delta 0.01
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Identifiers

Gene
BRCA2
Transcript
NM_000059.3
Coding (HGVS c.)
NM_000059.3:c.7685T>G
Protein (HGVS p.)
NP_000050.2:p.(Phe2562Cys)
GRCh38
chr13:32357809 T>G
GRCh37
chr13:32931946 T>G

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 lies in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30. REVEL is also high at 0.921, while SpliceAI is low at 0.01, supporting a damaging protein effect rather than a splice effect; together these findings support PP3 at supporting strength. Details ▾Hide ▴
Evidence considered
  • BRCA2 DNA-binding domain location
  • BayesDel no-AF 0.421539
  • REVEL 0.921
  • SpliceAI max delta 0.01
Sources
cspec ↗bayesdelrevelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP4 This missense variant is in the BRCA2 DNA-binding domain (amino acids 2481-3186), where ENIGMA applies BP4 only when BayesDel no-AF is less than or equal to 0.18 and SpliceAI is less than or equal to 0.1. SpliceAI is low at 0.01, but BayesDel is 0.421539, which is above the benign threshold and does not support BP4. Details ▾Hide ▴
Evidence considered
  • BRCA2 DNA-binding domain location
  • BayesDel no-AF 0.421539
  • SpliceAI max delta 0.01
Sources
cspec ↗bayesdelspliceai ↗vcep_specifications_v1_2_2024_11_18
BP7 N/ABP7 is intended for synonymous or certain intronic variants without splice impact and is not applicable to this missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • SpliceAI max delta 0.01
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.921. BayesDel score = 0.421539.

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 (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142784)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.921. BayesDel score = 0.421539.

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.