About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.341A>G, p.(His114Arg)
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Supporting
BS1 · supporting
BRCA2 BS1_Supporting is met because gnomAD v2.1 grpmax FAF is 7.443e-05, which is >0.00002 and ≤0.0001.
BP1Strong
BP1 · strong
BP1_Strong is met. p.(His114Arg) is a missense variant outside the BRCA2 clinically important functional domains defined by ENIGMA (aa 10-40 and aa 2481-3186), and SpliceAI predicts no significant splice impact (max delta 0.03 ≤0.1).
Recorded classification: Likely benign
ENIGMA BRCA2 VCEP ACMG/AMP qualitative combination rules. BP1_Strong is met, and BS1_Supporting is also met; this benign evidence supports a Likely benign classification.
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.
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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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: 2 met · 11 not met · 3 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant is BRCA2 NM_000059.4:c.341A>G, p.(His114Arg), a missense substitution at residue 114.
Under the BRCA2 ENIGMA specification, BP1_Strong applies to missense variants outside clinically important functional domains with no predicted splice impact. Residue 114 is outside the BRCA2 domains used by this framework (aa 10-40 and aa 2481-3186), and SpliceAI predicts no significant splice effect (max delta 0.03).
Population data support BS1_Supporting because gnomAD v2.1 grpmax FAF is 7.443e-05, which falls within the BRCA2 BS1_Supporting range (>0.00002 and ≤0.0001).
The ENIGMA multifactorial dataset does not support pathogenic enrichment: for c.341A>G the combined LR is 0.5897487000827281 and the sheet comments that the combined LR is not <0.5 or >2, so PS4/BS4-type multifactor evidence is not met.
No calibrated damaging or benign functional assay assignment for this variant was identified in the curated ENIGMA functional table, so PS3 and BS3 were not applied.
Overall, the assembled workspace supports a benign-leaning VCEP classification without conflicting pathogenic evidence sufficient to retain VUS; the best fit is Likely benign.
No criteria match.
Met · 2
BS1 SupportingBRCA2 BS1_Supporting is met because gnomAD v2.1 grpmax FAF is 7.443e-05, which is >0.00002 and ≤0.0001. Details ▾Hide ▴
Rule
BS1 Supporting for BRCA2: FAF >0.00002 and ≤0.0001 in gnomAD non-cancer datasets.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.442999999999999e-05.
- Variant also observed in gnomAD v4.1, supporting that it is not rare enough for PM2.
Sources
BP1 StrongBP1_Strong is met. p.(His114Arg) is a missense variant outside the BRCA2 clinically important functional domains defined by ENIGMA (aa 10-40 and aa 2481-3186), and SpliceAI predicts no significant splice impact (max delta 0.03 ≤0.1). Details ▾Hide ▴
Rule
Apply BP1_Strong to missense variants outside clinically important functional domains with SpliceAI ≤0.1.
Evidence considered
- Protein consequence is p.(His114Arg), residue 114.
- Clinically important BRCA2 domains for this rule are aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.03.
Sources
Not met · 11 · evaluated, threshold not reached
PS3 No calibrated damaging functional result for c.341A>G/p.(His114Arg) was found in ENIGMA BRCA2 Table 9, and the Parsons/ENIGMA multifactorial sheet does not provide damaging functional evidence for this variant. Details ▾Hide ▴
Rule
PS3 requires calibrated damaging functional evidence.
Evidence considered
- No direct match for c.341A>G/H114R was found in Specifications Table 9.
- HUMU SuppT1 row for c.341A>G shows no functional papers/category populated.
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_8vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1PMID:31131967 ↗
PS4 No qualifying case-control enrichment was demonstrated. In the ENIGMA multifactorial dataset, c.341A>G has no case-control LR populated and the combined LR is 0.5897487000827281, which does not support pathogenic enrichment. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals versus controls.
Evidence considered
- Parsons/ENIGMA SuppT1 row: case-control LR blank; combined LR 0.5897487000827281; comment says combined LR is not <0.5 or >2.
Sources
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1vcep_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_8cspec ↗PMID:31131967 ↗
PM2 Variant is present in gnomAD v2.1 and v4.1, so it is not absent from controls. Details ▾Hide ▴
Rule
PM2 Supporting requires absence from controls in gnomAD non-cancer datasets.
Evidence considered
- gnomAD v2.1 total AF 0.00010756372154541181, 27/251014 alleles, 1 homozygote.
- gnomAD v4.1 total AF 0.00003748158717030259.
Sources
PP1 No segregation LR supporting pathogenicity was assembled. Parsons/ENIGMA does not show a segregation LR for this variant. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation support.
Evidence considered
- HUMU SuppT1 row for c.341A>G has segregation LR blank.
Sources
PP3 PP3 is not met because p.(His114Arg) lies outside BRCA2 clinically important functional domains and SpliceAI is low (max delta 0.03, below the splicing threshold for PP3). Details ▾Hide ▴
Rule
PP3 requires either a qualifying missense prediction inside a clinically important domain or predicted splice impact with SpliceAI ≥0.2.
Evidence considered
- BRCA2 clinically important domains for this framework are aa 10-40 and aa 2481-3186; residue 114 is outside them.
- SpliceAI max delta score 0.03.
Sources
PP4 No multifactorial clinical LR meeting BRCA2 PP4 thresholds was assembled. Parsons/ENIGMA combined LR is 0.5897487000827281, below the pathogenic PP4 threshold. Details ▾Hide ▴
Rule
PP4 under BRCA2 ENIGMA is based on multifactorial LR favoring pathogenicity.
Evidence considered
- HUMU SuppT1 combined LR 0.5897487000827281.
Sources
BA1 gnomAD v2.1 grpmax FAF is 7.443e-05, below the BRCA2 BA1 threshold of >0.001. Details ▾Hide ▴
Rule
BA1 requires FAF >0.1% in a non-founder population.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.442999999999999e-05.
Sources
BS3 No calibrated benign functional result for c.341A>G/p.(His114Arg) was found in ENIGMA Table 9, and HUMU does not provide qualifying benign functional assay evidence for this variant. Details ▾Hide ▴
Rule
BS3 requires calibrated benign functional evidence.
Evidence considered
- No direct Table 9 match for c.341A>G/H114R.
- HUMU functional fields are unpopulated for this variant.
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_8vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1PMID:31131967 ↗
BS4 No quantitative non-segregation LR meeting BS4 thresholds was assembled. Parsons/ENIGMA shows no segregation LR for this variant, and combined LR is not low enough for BS4. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- HUMU SuppT1 segregation LR blank.
- Combined LR 0.5897487000827281 is above the BS4_Supporting threshold (≤0.48).
Sources
BP4 BP4 is restricted to variants inside BRCA2 clinically important functional domains with no predicted impact; residue 114 is outside those domains, so BP4 is not the correct benign code here. Details ▾Hide ▴
Rule
For missense BRCA2 variants outside domains, ENIGMA routes benign bioinformatic evidence to BP1_Strong rather than BP4.
Evidence considered
- Residue 114 is outside aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.03.
Sources
BP5 No multifactorial LR against pathogenicity meeting BP5 thresholds was assembled. Parsons/ENIGMA combined LR is 0.5897487000827281, which is above the BP5 threshold range. Details ▾Hide ▴
Rule
BP5 under BRCA2 ENIGMA is based on multifactorial LR against pathogenicity.
Evidence considered
- HUMU SuppT1 combined LR 0.5897487000827281.
Sources
Not assessed · 3 · no assessment recorded
PS1 No workspace evidence identified a different nucleotide change with the same amino-acid or same splicing outcome already classified pathogenic/likely pathogenic under BRCA2 ENIGMA rules. Details ▾Hide ▴
Rule
PS1 requires an established pathogenic/likely pathogenic reference variant with the same protein or splicing consequence.
Evidence considered
- Variant is missense with low predicted splice impact.
Still missing
- No explicit Table 5 lookup for alternate codons producing p.His114Arg was present in the assembled workspace.
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___2___2_0_2_4___1_1___1_8
PM3 No Fanconi anemia proband/co-occurrence evidence was assembled for this case. Details ▾Hide ▴
Rule
PM3 in BRCA2 is specific to BRCA2-related Fanconi anemia contexts.
Evidence considered
- Workspace contains no PM3-style FA case evidence.
Still missing
- No phenotype/proband-level recessive BRCA2 evidence in the workspace.
Sources
BS2 No phenotype-resolved biallelic/proband data relevant to BRCA2-related Fanconi anemia were assembled; population homozygotes alone do not establish BS2 under the BRCA2 specification. Details ▾Hide ▴
Rule
BS2 requires specified recessive-disease context evidence, not just population counts.
Evidence considered
- Homozygotes are present in gnomAD, but no accompanying absence-of-FA clinical data is available.
Still missing
- No Table 8-style proband-level BS2 evidence in the workspace.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant p.(His114Arg); BRCA2 PVS1 rules apply to null variants or RNA-only evidence causing loss of function, which is not the case here. Details ▾Hide ▴
Rule
PVS1 is not used for missense substitutions without qualifying RNA LOF evidence.
Evidence considered
- NM_000059.4:c.341A>G encodes BRCA2 p.(His114Arg).
- BRCA2 ENIGMA PVS1 is restricted to null/RNA LOF contexts.
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___2___2_0_2_4___1_1___1_8
PS2 N/ABRCA2 ENIGMA marks PS2 as not applicable. Details ▾Hide ▴
PM1 N/ABRCA2 ENIGMA marks PM1 as not applicable; domain/location information is instead incorporated into the BRCA-specific BP1/BP4/PP3 framework. Details ▾Hide ▴
Evidence considered
- CSPEC applicability lists PM1 as not applicable.
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___2___2_0_2_4___1_1___1_8
PM4 N/ABRCA2 ENIGMA marks PM4 as not applicable. Details ▾Hide ▴
PM5 N/ABRCA2 PM5 in this specification is for PTC variants in eligible exons; this variant is missense. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5 applies to proven pathogenic PTC analogs, not missense substitutions.
Evidence considered
- Variant is missense in exon 4, not a protein-truncating variant.
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/ABRCA2 ENIGMA marks PM6 as not applicable. Details ▾Hide ▴
PP2 N/ABRCA2 ENIGMA marks PP2 as not applicable. Details ▾Hide ▴
PP5 N/ABRCA2 ENIGMA marks PP5 as not applicable. Details ▾Hide ▴
BP2 N/ABRCA2 ENIGMA marks BP2 as not applicable except within BS2 context, which is not established here. Details ▾Hide ▴
BP3 N/ABRCA2 ENIGMA marks BP3 as not applicable. Details ▾Hide ▴
BP6 N/ABRCA2 ENIGMA marks BP6 as not applicable. Details ▾Hide ▴
BP7 N/ABP7 is for silent/intronic or RNA-only benign evidence contexts; this variant is missense. Details ▾Hide ▴
Rule
BP7 does not apply to this missense substitution.
Evidence considered
- Variant is missense p.(His114Arg), not synonymous/intronic.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.341A>G
- Protein (HGVS p.)
- NP_000050.3:p.(His114Arg)
- GRCh38
- chr13:32325100 A>G
- GRCh37
- chr13:32899237 A>G
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 |
|---|
Statements
No population statements were recorded.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 is not met because p.(His114Arg) lies outside BRCA2 clinically important functional domains and SpliceAI is low (max delta 0.03, below the splicing threshold for PP3). Details ▾Hide ▴
Rule
PP3 requires either a qualifying missense prediction inside a clinically important domain or predicted splice impact with SpliceAI ≥0.2.
Evidence considered
- BRCA2 clinically important domains for this framework are aa 10-40 and aa 2481-3186; residue 114 is outside them.
- SpliceAI max delta score 0.03.
Sources
BP4 BP4 is restricted to variants inside BRCA2 clinically important functional domains with no predicted impact; residue 114 is outside those domains, so BP4 is not the correct benign code here. Details ▾Hide ▴
Rule
For missense BRCA2 variants outside domains, ENIGMA routes benign bioinformatic evidence to BP1_Strong rather than BP4.
Evidence considered
- Residue 114 is outside aa 10-40 and aa 2481-3186.
- SpliceAI max delta score 0.03.
Sources
BP7 N/ABP7 is for silent/intronic or RNA-only benign evidence contexts; this variant is missense. Details ▾Hide ▴
Rule
BP7 does not apply to this missense substitution.
Evidence considered
- Variant is missense p.(His114Arg), not synonymous/intronic.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535438831
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/51460/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32899237-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32325100-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.341A…
- OncoKB ↗www.oncokb.org/gene/BRCA2/H114R
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 Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).