About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.6495G>A, p.(Leu2165=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 (non-cancer, exome subset), gnomAD v3.1/v4.1 (non-cancer), and gnomAD-Canada v1.0, consistent with PM2_Supporting under ENIGMA BRCA2 v1.2 (absent from outbred population controls).
Benign criteria applied · 1
BP1Strong
BP1 · strong
Silent substitution (p.Leu2165=) located outside the clinically important functional domains of BRCA2 (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186), and no splicing predicted (SpliceAI max delta = 0.04, ≤0.1). Meets ENIGMA BP1_Strong criteria.
Recorded classification: Likely benign
ENIGMA BRCA2 v1.2 Table 3 conflicting-evidence point system: BP1_Strong (-4) + PM2_Supporting (+1) = -3 points, which falls in the Likely Benign range (-6 to -2). The naive combination rules do not apply because both benign and pathogenic criteria are met, triggering the explicit conflicting-evidence point-system override.
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.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 11 not met · 2 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000059.4:c.6495G>A (p.Leu2165=) is a synonymous substitution in BRCA2 exon 11, located outside the clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186).
SpliceAI predicts no splicing impact (max delta score = 0.04), consistent with a silent variant that does not alter the mRNA transcript.
BP1_Strong is met: silent substitution outside clinically important functional domains with no splicing predicted (SpliceAI ≤0.1). This provides strong evidence toward a benign interpretation.
PM2_Supporting is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in outbred population controls. However, for a synonymous variant with no predicted functional consequence, population absence is more consistent with a rare benign polymorphism than with pathogenicity.
Under ENIGMA BRCA2 v1.2 Table 3 combination rules, BP1_Strong alone does not reach Likely Benign (which requires Strong Benign + Supporting Benign or Moderate Benign + Supporting Benign). With PM2_Supporting pointing in the pathogenic direction, the net classification is Variant of Uncertain Significance (VUS).
This variant has been reported in ClinVar as Likely benign by two clinical laboratories (VariationID 433804, criteria provided, single submitter), consistent with the overall benign direction of evidence.
No criteria match.
Met · 2
PM2 SupportingVariant is absent from gnomAD v2.1 (non-cancer, exome subset), gnomAD v3.1/v4.1 (non-cancer), and gnomAD-Canada v1.0, consistent with PM2_Supporting under ENIGMA BRCA2 v1.2 (absent from outbred population controls). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome
- non-cancer).
- Absent from gnomAD v4.1 (exome
- Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
BP1 StrongSilent substitution (p.Leu2165=) located outside the clinically important functional domains of BRCA2 (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186), and no splicing predicted (SpliceAI max delta = 0.04, ≤0.1). Meets ENIGMA BP1_Strong criteria. Details ▾Hide ▴
Evidence considered
- Variant is a synonymous substitution at codon 2165 (p.Leu2165=)
- located outside the PALB2 binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186).
- SpliceAI max delta = 0.04
- no splicing impact predicted.
Sources
Not met · 11 · evaluated, threshold not reached
PS4 No case-control study demonstrates a statistically significant excess of this variant in affected individuals versus controls (OR ≥4 with lower CI excluding 2.0, p≤0.05). ClinVar reports Likely benign classification by two clinical laboratories but provides no case counts. Details ▾Hide ▴
Evidence considered
- ClinVar classification Likely benign (VariationID 433804) by 2 clinical laboratories suggests absence of disease association
- but no case-control statistics are available.
Still missing
- No published case-control or cohort study reports allele counts in affected vs. unaffected individuals.
Sources
PP1 No co-segregation data available. No published family-based segregation analysis has been performed for this variant, and no LR meeting the PP1 threshold (≥2.08) is available from ENIGMA resources. Details ▾Hide ▴
Still missing
- No co-segregation analysis or family studies published for this variant.
PP3 ENIGMA PP3 requires either (a) missense/in-frame variant inside a clinically important functional domain with BayesDel no-AF ≥0.30, or (b) SpliceAI ≥0.2 for any silent/missense/in-frame variant. This variant is silent, outside the functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI max delta is 0.04 (<0.2). Neither condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.04 (DS_AG=0.04
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.01)
- well below the 0.2 threshold for splicing prediction.
- REVEL and BayesDel scores not applicable/not found for this synonymous variant.
Sources
PP4 Variant not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. No clinical-history likelihood ratio supporting pathogenicity (LR ≥2.08) is available. Details ▾Hide ▴
Evidence considered
- Searched PMID_31853058_BRCA2_clinical_history_LR.xlsx for c.6495G>A
- not present. No clinical-history LR available.
Still missing
- Not present in Li et al. 2020 clinical-history LR dataset.
Sources
BA1 ENIGMA BA1 requires filter allele frequency (FAF) > 0.001 in gnomAD non-cancer, non-founder populations. Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada. FAF = 0.
Sources
BS1 ENIGMA BS1 requires FAF > 0.0001 (Strong) or > 0.00002 (Supporting). Variant is absent from all gnomAD populations. Does not meet BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada.
Sources
BS2 ENIGMA BS2 requires observation of the variant in trans with a known pathogenic variant in an individual without Fanconi Anemia phenotype. No such proband data are available, and no homozygous observations exist in gnomAD. Details ▾Hide ▴
Still missing
- No proband-level data available to assess trans configuration or Fanconi Anemia phenotype.
BS4 No lack-of-segregation data available. No published family study demonstrates absence of co-segregation, and no negative LOD score data are available from ENIGMA resources. Details ▾Hide ▴
Still missing
- No family-based segregation data published for this variant.
BP5 Variant not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. No clinical-history likelihood ratio supporting benignity (LR ≤0.48) is available. Details ▾Hide ▴
Evidence considered
- Searched PMID_31853058_BRCA2_clinical_history_LR.xlsx for c.6495G>A
- not present.
Still missing
- Not present in Li et al. 2020 clinical-history LR dataset.
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established in vitro or in vivo functional studies demonstrating no effect on mRNA transcript profile. No such studies exist for this variant. BP7_Supporting requires a silent variant inside a clinically important functional domain with BP4 met, which does not apply (codon 2165 is outside functional domains). Details ▾Hide ▴
Still missing
- No mRNA assay data (e.g.
- RT-PCR
- minigene splicing assay) available for BP7_Strong (RNA) application.
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Likely benign, and no publication asserts pathogenicity for c.6495G>A. Details ▾Hide ▴
Not assessed · 2 · no assessment recorded
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect on protein function have been identified for this variant. The variant is not listed in ENIGMA Specifications Table 9 (curated functional assay results). Details ▾Hide ▴
Still missing
- No published functional studies (cDNA complementation
- targeted protein or mRNA assays) have tested c.6495G>A for damaging effect.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function have been identified. The variant is not listed in ENIGMA Specifications Table 9. In silico SpliceAI predictions alone are insufficient for BS3 under ENIGMA rules. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splice impact (max delta = 0.04)
- but in silico prediction alone does not meet the 'well-established functional studies' requirement for BS3.
Still missing
- No in vitro functional assay (e.g.
- RT-PCR
- minigene reporter) directly demonstrating absence of splicing effect for this variant.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.Leu2165=); PVS1 under ENIGMA BRCA2 v1.2 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). Details ▾Hide ▴
No further detail was recorded.
PS1 N/ASynonymous variant; PS1 under ENIGMA BRCA2 v1.2 applies only to missense substitutions with a same-residue known pathogenic comparator or to variants with same predicted splicing impact as a known pathogenic variant. SpliceAI max delta is 0.04, well below the 0.2 threshold for splicing prediction. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPENIGMA BRCA2 v1.2 specification marks PS2 as Not Applicable; de novo data are not considered for BRCA2 variant classification under this framework. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPENIGMA BRCA2 v1.2 specification marks PM1 as Not Applicable for BRCA2. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per instruction. No Fanconi Anemia phenotype or trans configuration data available. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPENIGMA BRCA2 v1.2 specification marks PM4 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ASynonymous variant; ENIGMA PM5 is repurposed for PTC (protein termination codon) variants in exons where proven pathogenic PTC variants exist. This variant does not introduce a premature termination codon. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPENIGMA BRCA2 v1.2 specification marks PM6 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPENIGMA BRCA2 v1.2 specification marks PP2 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPENIGMA BRCA2 v1.2 specification marks PP5 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPENIGMA BRCA2 v1.2 specification marks BP2 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPENIGMA BRCA2 v1.2 specification marks BP3 as Not Applicable; in-frame deletions/insertions only, not applicable to this synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AENIGMA BP4 applies to silent variants only when inside a clinically important functional domain. Codon 2165 is outside both the PALB2 binding domain (aa 10-40) and the DNA-binding domain (aa 2481-3186). BP4 criteria are not met for silent variants outside functional domains under ENIGMA v1.2. BP1_Strong captures the benign evidence for this variant class. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPENIGMA BRCA2 v1.2 specification marks BP6 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.6495G>A
- Protein (HGVS p.)
- NP_000050.3:p.(Leu2165=)
- GRCh38
- chr13:32340850 G>A
- GRCh37
- chr13:32914987 G>A
- ClinVar
- 433804
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
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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
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ENIGMA PP3 requires either (a) missense/in-frame variant inside a clinically important functional domain with BayesDel no-AF ≥0.30, or (b) SpliceAI ≥0.2 for any silent/missense/in-frame variant. This variant is silent, outside the functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI max delta is 0.04 (<0.2). Neither condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.04 (DS_AG=0.04
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.01)
- well below the 0.2 threshold for splicing prediction.
- REVEL and BayesDel scores not applicable/not found for this synonymous variant.
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established in vitro or in vivo functional studies demonstrating no effect on mRNA transcript profile. No such studies exist for this variant. BP7_Supporting requires a silent variant inside a clinically important functional domain with BP4 met, which does not apply (codon 2165 is outside functional domains). Details ▾Hide ▴
Still missing
- No mRNA assay data (e.g.
- RT-PCR
- minigene splicing assay) available for BP7_Strong (RNA) application.
BP4 N/AENIGMA BP4 applies to silent variants only when inside a clinically important functional domain. Codon 2165 is outside both the PALB2 binding domain (aa 10-40) and the DNA-binding domain (aa 2481-3186). BP4 criteria are not met for silent variants outside functional domains under ENIGMA v1.2. BP1_Strong captures the benign evidence for this variant class. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
7 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
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PMID 25741868 ↗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.Richards S et al. · 2015This is the ACMG/AMP standards and guidelines for interpretation of sequence variants. It provides the general classification framework and criteria definitions but does not discuss any specific BRCA2 variants, including NM_000059.4:c.6495G>A.Does not name this variant
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Discusses general criteria for genetic counseling referral in hereditary cancer syndromes. Does not mention BRCA2 c.6495G>A or any specific BRCA2 variants.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on breast and gynecologic cancers. Provides general overview of hereditary breast cancer genetics. Does not mention BRCA2 c.6495G>A.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ summary on cancer genetics risk assessment and counseling. General educational resource about genetic counseling processes. Does not mention BRCA2 c.6495G>A.Does not name this variant
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PMID 29939840 ↗Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.Ramakrishna N et al. · 2018ASCO clinical practice guideline on management of HER2-positive breast cancer with brain metastases. Discusses treatment recommendations for advanced breast cancer. Does not mention BRCA2 c.6495G>A.Does not name this variant
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PMID 30452337 ↗Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update.Burstein HJ et al. · 2019ASCO clinical practice guideline focused update on adjuvant endocrine therapy for hormone receptor-positive breast cancer. Discusses duration of aromatase inhibitor therapy. Does not mention BRCA2 c.6495G>A.Does not name this variant
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PMID 31479144 ↗Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement.US Preventive Services Task Force et al. · 2019US Preventive Services Task Force recommendation on medication use to reduce breast cancer risk. Discusses risk-reducing medications for breast cancer prevention. Does not mention BRCA2 c.6495G>A.Does not name this variant
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 0.040
Open source ↗
ClinVar
2 Likely benign
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535438831
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/433804/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32914987-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32340850-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32340850-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.6495…
- OncoKB ↗www.oncokb.org/gene/BRCA2/L2165=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.6495G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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 Likely benign (2 clinical laboratories). (ClinVarID = 433804)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.