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BRCA2c.4071A>CBenign
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Variant interpretation report

BRCA2 c.4071A>C, p.(Leu1357=)

NM_000059.4:c.4071A>C NP_000050.3:p.(Leu1357=) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A benign 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: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

BA1 is met because the variant exceeds the BRCA2 ENIGMA BA1 filter allele frequency threshold (>0.001) in non-founder population data. In gnomAD v2.1 the grpmax FAF is 0.00161392, and in gnomAD v4.1 the grpmax FAF is 0.00154091, both above the stand-alone benign threshold.

BS1Strong
BS1 · strong

BS1 is also met because the variant's gnomAD filter allele frequency is well above the BRCA2 ENIGMA BS1 strong threshold (>0.0001). This is redundant once BA1 is met but remains concordant benign evidence.

BP1Strong
BP1 · strong

BP1_Strong is met under BRCA2 ENIGMA because this is a silent substitution, p.(Leu1357=), outside the BRCA2 clinically important domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00, <=0.1).

Recorded classification: Benign

ENIGMA BRCA2 ACMG/AMP v1.2 qualitative classification. BA1 (Stand Alone) is sufficient for Benign; BS1 (Strong) and BP1_Strong are concordant additional benign evidence.

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.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
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: 3 met · 2 not met · 10 not assessed · 13 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

BRCA2 ENIGMA BA1 is met because the variant exceeds the stand-alone benign frequency threshold in gnomAD: v2.1 grpmax FAF 0.00161392 and v4.1 grpmax FAF 0.00154091, both >0.001.

The variant is synonymous, p.(Leu1357=), and lies outside the BRCA2 clinically important domains defined by ENIGMA; with SpliceAI max delta score 0.00, this satisfies BP1_Strong.

ClinVar shows a concordant benign expert-panel assertion from ENIGMA, which supports but does not replace the VCEP rule-based classification.

Met · 3

BA1 Stand aloneBA1 is met because the variant exceeds the BRCA2 ENIGMA BA1 filter allele frequency threshold (>0.001) in non-founder population data. In gnomAD v2.1 the grpmax FAF is 0.00161392, and in gnomAD v4.1 the grpmax FAF is 0.00154091, both above the stand-alone benign threshold. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BA1: Filter allele frequency >0.1% (FAF >0.001) in gnomAD non-founder population(s).
Evidence considered
  • gnomAD v2.1 grpmax FAF 0.00161392 in African/African American population.
  • gnomAD v4.1 grpmax FAF 0.00154091; total AF 8.51244e-05, 137/1609410 alleles.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 StrongBS1 is also met because the variant's gnomAD filter allele frequency is well above the BRCA2 ENIGMA BS1 strong threshold (>0.0001). This is redundant once BA1 is met but remains concordant benign evidence. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS1 Strong: FAF >0.0001 in gnomAD non-founder population(s).
Evidence considered
  • gnomAD v2.1 grpmax FAF 0.00161392.
  • gnomAD v4.1 grpmax FAF 0.00154091.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BP1 StrongBP1_Strong is met under BRCA2 ENIGMA because this is a silent substitution, p.(Leu1357=), outside the BRCA2 clinically important domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00, <=0.1). Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP1_Strong: silent substitution outside clinically important functional domains and no predicted splicing effect (SpliceAI <=0.1).
Evidence considered
  • Protein consequence p.(Leu1357=) / p.(L1357=).
  • SpliceAI max delta score 0.00.
Sources
cspec ↗spliceai ↗

Not met · 2 · evaluated, threshold not reached

PM2 The variant is not absent from controls; it is observed repeatedly in gnomAD v2.1 and v4.1. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from controls in gnomAD.
Evidence considered
  • gnomAD v2.1 total AF 0.000179313, 50/278842 alleles; gnomAD v4.1 total AF 8.51244e-05, 137/1609410 alleles.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
PP3 SpliceAI max delta score is 0.00, far below the BRCA2 ENIGMA PP3 splicing threshold of >=0.2; the variant is synonymous, not a missense/in-frame protein-altering change. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 for splicing requires SpliceAI >=0.2.
Evidence considered
  • SpliceAI DS_AG/AL/DG/DL all 0.0; max delta score 0.00.
Sources
spliceai ↗cspec ↗

Not assessed · 10 · no assessment recorded

PS3 No calibrated functional assay evidence for this specific variant was identified in the reviewed workspace or VCEP functional table. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence.
Evidence considered
  • Reviewed BRCA1/2 VCEP functional assay table; no variant-specific entry found for c.4071A>C / p.(Leu1357=).
Still missing
  • No variant-specific functional assay result located in Specifications Table 9 or other reviewed materials.
Sources
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
PS4 No qualifying case-control enrichment or ENIGMA quantitative pathogenic likelihood evidence for this specific variant was identified in the reviewed workspace/VCEP files. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS4 requires significant affected-vs-control enrichment.
Evidence considered
  • PS4 requires significant enrichment in affected individuals; no variant-specific PS4 evidence located.
Still missing
  • No qualifying PS4 case-control dataset or ENIGMA LR specific to this variant found.
Sources
cspec ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8
PM3 No Fanconi-anemia-related biallelic case evidence or phase data were identified. Details ▾Hide ▴
Rule
PM3 requires BRCA2-related Fanconi anemia context with co-occurring variants.
Evidence considered
  • PM3 in BRCA2 ENIGMA depends on FA phenotype with co-occurring variants and point assignment.
Still missing
  • No recessive FA phenotype/phase evidence in workspace.
Sources
cspec ↗
PP1 No quantitative segregation data were identified for this case. Details ▾Hide ▴
Rule
PP1 requires quantitative cosegregation evidence.
Evidence considered
  • PP1 in BRCA2 ENIGMA requires quantified segregation likelihood ratios.
Still missing
  • No family segregation LR available.
Sources
cspec ↗
PP4 No multifactorial clinical LR supporting pathogenicity was identified for this specific variant. Details ▾Hide ▴
Rule
PP4 requires combined pathogenic LR from multifactorial clinical data.
Evidence considered
  • PP4 in BRCA2 ENIGMA is reserved for multifactorial clinical likelihood data.
Still missing
  • No quantitative multifactorial LR in workspace for PP4.
Sources
cspec ↗
BS2 No point-based adult observation data without Fanconi anemia features were assembled for this case. Details ▾Hide ▴
Rule
BS2 requires qualifying observation data and point assignment.
Evidence considered
  • BS2 under BRCA2 ENIGMA requires point-based evidence from observations lacking FA phenotype.
Still missing
  • No BS2 point-assignment data in workspace.
Sources
cspec ↗
BS3 No calibrated benign functional assay result for this specific variant was identified. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
  • Reviewed BRCA1/2 VCEP functional assay table; no c.4071A>C entry identified.
Still missing
  • No variant-specific BS3 functional assay entry located.
Sources
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
BS4 No quantitative non-segregation likelihood ratio was identified for this variant. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
  • BS4 requires quantitative lack-of-segregation evidence; none was found in reviewed materials.
Still missing
  • No BS4 segregation LR located.
Sources
cspec ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8
BP5 No quantitative multifactorial likelihood ratio against pathogenicity was assembled for this variant. Details ▾Hide ▴
Rule
BP5 requires combined LR against pathogenicity from multifactorial data.
Evidence considered
  • BP5 in BRCA2 ENIGMA is reserved for benign multifactorial clinical likelihood data.
Still missing
  • No BP5 multifactorial LR in workspace.
Sources
cspec ↗
BP7 No qualifying RNA assay evidence was identified. Computational splice neutrality alone does not satisfy the BRCA2 ENIGMA BP7 RNA rule, and the BP7 supporting silent-variant rule is for silent variants inside clinically important domains if BP4 is met. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 depends on qualifying RNA evidence, or on silent variants inside clinically important domains if BP4 is met.
Evidence considered
  • SpliceAI predicts no splice impact, but no RNA assay was identified.
Still missing
  • No variant-specific RNA assay demonstrating no transcript impact.
Sources
cspec ↗spliceai ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous exonic variant p.(Leu1357=) is not a null/splice-donor/acceptor +/-1,2 variant and there is no RNA evidence showing a loss-of-function transcript effect. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PVS1 is for null variants or qualifying mRNA loss-of-function evidence.
Evidence considered
  • BRCA2 ENIGMA VCEP PVS1 applies to null variants or qualifying RNA loss-of-function evidence; this variant is synonymous with SpliceAI max delta 0.00.
Sources
cspec ↗spliceai ↗
PS1 N/ANo evidence that this synonymous change has the same proven pathogenic splicing consequence as another pathogenic variant, and the missense-based PS1 rule does not apply. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS1 requires same pathogenic amino-acid substitution or same pathogenic splice effect.
Evidence considered
  • PS1 under BRCA2 ENIGMA is for same amino-acid change in missense context or same proven splice effect; SpliceAI predicts no splice impact here.
Sources
cspec ↗spliceai ↗
PS2 N/AMarked not applicable in the BRCA2 ENIGMA specification for this framework. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists PS2 as not applicable.
Sources
cspec ↗
PM1 N/APM1 is marked not applicable in BRCA2 ENIGMA and this synonymous variant is outside the clinically important domains noted for bioinformatic missense evaluation. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC marks PM1 not applicable.
Sources
cspec ↗
PM4 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists PM4 as not applicable.
Sources
cspec ↗
PM5 N/AThis is not a protein-terminating variant and not a qualifying missense substitution for PM5/PM5_PTC. Details ▾Hide ▴
Rule
PM5 requires qualifying missense or PTC context.
Evidence considered
  • PM5 in BRCA2 ENIGMA is used for qualifying missense comparisons or PTC variants by exon; neither applies here.
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
PM6 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists PM6 as not applicable.
Sources
cspec ↗
PP2 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists PP2 as not applicable.
Sources
cspec ↗
PP5 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists PP5 as not applicable.
Sources
cspec ↗
BP2 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists BP2 as not applicable.
Sources
cspec ↗
BP3 N/AMarked not applicable in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists BP3 as not applicable.
Sources
cspec ↗
BP4 N/AFor BRCA2 ENIGMA, BP4 silent-variant use is defined for silent variants inside clinically important domains with no splice impact. This variant is outside those domains, so BP1_Strong rather than BP4 is the relevant benign bioinformatic code. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 silent rule is for silent variants inside clinically important domains with SpliceAI <=0.1.
Evidence considered
  • Variant is silent and outside aa 10-40 and aa 2481-3186; SpliceAI max delta 0.00.
Sources
cspec ↗spliceai ↗
BP6 N/AMarked not applicable in the BRCA2 ENIGMA specification; external assertions such as ClinVar are not used as BP6 in this framework. Details ▾Hide ▴
Rule
Not applicable per BRCA2 ENIGMA specification.
Evidence considered
  • CSPEC lists BP6 as not applicable; ClinVar benign expert-panel assertion is treated as concordant context, not BP6 evidence.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.4071A>C
Protein (HGVS p.)
NP_000050.3:p.(Leu1357=)
GRCh38
chr13:32338426 A>C
GRCh37
chr13:32912563 A>C

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…

Statements

No population statements were recorded.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI max delta score is 0.00, far below the BRCA2 ENIGMA PP3 splicing threshold of >=0.2; the variant is synonymous, not a missense/in-frame protein-altering change. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 for splicing requires SpliceAI >=0.2.
Evidence considered
  • SpliceAI DS_AG/AL/DG/DL all 0.0; max delta score 0.00.
Sources
spliceai ↗cspec ↗
BP7 No qualifying RNA assay evidence was identified. Computational splice neutrality alone does not satisfy the BRCA2 ENIGMA BP7 RNA rule, and the BP7 supporting silent-variant rule is for silent variants inside clinically important domains if BP4 is met. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 depends on qualifying RNA evidence, or on silent variants inside clinically important domains if BP4 is met.
Evidence considered
  • SpliceAI predicts no splice impact, but no RNA assay was identified.
Still missing
  • No variant-specific RNA assay demonstrating no transcript impact.
Sources
cspec ↗spliceai ↗
BP4 N/AFor BRCA2 ENIGMA, BP4 silent-variant use is defined for silent variants inside clinically important domains with no splice impact. This variant is outside those domains, so BP1_Strong rather than BP4 is the relevant benign bioinformatic code. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 silent rule is for silent variants inside clinically important domains with SpliceAI <=0.1.
Evidence considered
  • Variant is silent and outside aa 10-40 and aa 2481-3186; SpliceAI max delta 0.00.
Sources
cspec ↗spliceai ↗

Statement

In silico

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

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
Cancer hotspots Captured Cancer Hotspots source record
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.

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

In silico

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

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).