About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.750G>A, p.(Val250=)
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Supporting
BS1 · supporting
BS1_Supporting per ENIGMA is met. The filter allele frequency (FAF) in gnomAD v2.1 (non-cancer, exome only) is 4.75e-05 (0.00475%), which falls in the range FAF > 0.00002 (0.002%) and ≤ 0.0001 (0.01%). The highest population sub-frequency is in European (non-Finnish) at AF=7.77e-05 (10/128,766 alleles, 0 homozygotes). The variant is also present in gnomAD v4.1 with grpmax FAF 9.28e-05, consistent with the BS1_Supporting range. This frequency is higher than expected for a highly penetrant pathogenic BRCA2 variant.
BP1Strong
BP1 · strong
BP1_Strong per ENIGMA is met. c.750G>A is a silent (synonymous) substitution located at Val250, which is outside both BRCA2 clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186). SpliceAI predicts no splicing impact (max delta score = 0.00, well below the 0.1 threshold). The ENIGMA specification states: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤ 0.1).' All conditions are satisfied.
BP6Supporting
BP6 · supporting
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.
Recorded classification: Likely benign
ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3 combination rules applied to adjudicated criteria. One Strong Benign criterion (BP1_Strong) plus two Supporting Benign criteria (BS1_Supporting, BP6_Supporting) independently satisfy multiple Likely Benign rules: 1 Strong (Benign) + 1 Supporting (Benign) and 2 Supporting (Benign). No pathogenic criteria are met; no conflicting evidence present. ENIGMA point system (conflicting_evidence only) confirms: BP1_Strong (-4) + BS1_Supporting (-1) + BP6_Supporting (-1) = -6, within Likely Benign range (-6 to -2). ClinVar expert panel (ENIGMA) also reports Likely Benign (ClinVar ID 135814).
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
134 / 1,613,406 alleles
gnomAD v4.1: 134 / 1,613,406 alleles. Recorded AF 8.30541e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89734e-05; MAF= 0.00390%, 11/282244 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76603e-05; MAF= 0.00777%, 10/128766 alleles, homozygotes = 0); grpmax FAF= 4.75e-05.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
17 reported laboratory submissions
10 Likely benign · 5 Benign · 1 Likely Benign · 1 likely benign.
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.
27 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
BP1_Strong is met: c.750G>A is a silent (synonymous) substitution (p.Val250=) located outside both BRCA2 clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1 threshold).
BS1_Supporting is met: the gnomAD v2.1 non-cancer exome filter allele frequency (FAF) is 4.75e-05 (0.00475%), falling in the ENIGMA BS1_Supporting range (FAF > 0.002% and ≤ 0.01%). The highest population sub-frequency is in European (non-Finnish) at 7.77e-05 (10/128,766 alleles).
PM2_Supporting is not met because the variant is present in gnomAD population databases (11 alleles in v2.1, 134 alleles in v4.1), failing the ENIGMA requirement of absence from outbred population controls.
PP3 is not met: SpliceAI max delta is 0.00 (< 0.2) and the variant is outside clinically important functional domains, failing both PP3 application pathways in the ENIGMA specification.
BA1 (Stand-Alone Benign) is not met: gnomAD grpmax FAF of 4.75e-05 (v2.1) and 9.28e-05 (v4.1) are both well below the 0.1% (FAF > 0.001) threshold.
BS3, BS4, PP1, PP4, BP5, and BP7 are not assessed due to absence of variant-specific functional, segregation, or clinical-history LR data in the ENIGMA VCEP-curated datasets (Table 9, clinical_history_LR.xlsx, HUMU-40-1557-s001, ST7).
PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP2, PP5, BP2, BP3, BP6 are not applicable for this synonymous variant under the ENIGMA VCEP framework.
Under the ENIGMA Table 3 combination rules, 1 Strong Benign criterion (BP1_Strong) plus 1 Supporting Benign criterion (BS1_Supporting) reaches the threshold for Likely Benign. Under the ENIGMA point system: BP1_Strong = -4 points, BS1_Supporting = -1 point, total = -5 points (Likely Benign range: -6 to -2).
ClinVar lists this variant as Likely Benign with expert panel review status by ENIGMA (ClinVar ID 135814), with 10 clinical laboratories reporting Likely Benign and 5 reporting Benign. This clinical consensus is concordant with the ENIGMA framework-based assessment.
No criteria match.
Met · 3
BS1 SupportingBS1_Supporting per ENIGMA is met. The filter allele frequency (FAF) in gnomAD v2.1 (non-cancer, exome only) is 4.75e-05 (0.00475%), which falls in the range FAF > 0.00002 (0.002%) and ≤ 0.0001 (0.01%). The highest population sub-frequency is in European (non-Finnish) at AF=7.77e-05 (10/128,766 alleles, 0 homozygotes). The variant is also present in gnomAD v4.1 with grpmax FAF 9.28e-05, consistent with the BS1_Supporting range. This frequency is higher than expected for a highly penetrant pathogenic BRCA2 variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 exome non-cancer grpmax FAF = 4.75e-05 (0.00475%)
- within BS1_Supporting range (>0.002% and ≤0.01%)
- 10/128
- 766 NFE alleles
- 0 homozygotes observed
- gnomAD v4.1 grpmax FAF = 9.28e-05
- also in BS1_Supporting range
Sources
BP1 StrongBP1_Strong per ENIGMA is met. c.750G>A is a silent (synonymous) substitution located at Val250, which is outside both BRCA2 clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186). SpliceAI predicts no splicing impact (max delta score = 0.00, well below the 0.1 threshold). The ENIGMA specification states: 'Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤ 0.1).' All conditions are satisfied. Details ▾Hide ▴
Evidence considered
- Silent (synonymous) substitution p.Val250=
- V250 is outside BRCA2 clinically important domains (PALB2: aa10-40
- DNA binding: aa2481-3186)
- SpliceAI max delta = 0.00 (≤ 0.1)
- ENIGMA Figure 1A and Appendix J define BP1_Strong for this variant class
Sources
Not met · 4 · evaluated, threshold not reached
PM2 PM2_Supporting per ENIGMA requires the variant to be absent from gnomAD v2.1 (non-cancer, exome only) AND gnomAD v3.1 (non-cancer). c.750G>A is present in gnomAD v2.1 at AF=3.9e-05 (11/282,244 alleles) and in gnomAD v4.1 at AF=8.3e-05 (134/1,613,406 alleles). The variant is not absent from population controls, so PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 11 alleles (AF=3.9e-05
- exome 10 alleles in 250
- 922)
- gnomAD v4.1: 134 alleles (AF=8.3e-05)
- Variant is present
- not absent
- so PM2_Supporting not satisfied
Sources
PP3 PP3 per ENIGMA 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 variant type regardless of location. c.750G>A is synonymous and located at Val250, which is outside both clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186). SpliceAI max delta score is 0.00, well below the 0.2 threshold. BayesDel score was not available. PP3 is not met under either pathway. Details ▾Hide ▴
Evidence considered
- V250 is outside BRCA2 clinically important functional domains (aa10-40
- aa2481-3186)
- SpliceAI max delta = 0.00 (< 0.2 threshold)
- No BayesDel score available
- REVEL also not found
Sources
BA1 BA1 (Stand-Alone Benign) per ENIGMA requires filter allele frequency (FAF) > 0.001 (0.1%) in gnomAD non-cancer, non-founder populations. The gnomAD v2.1 grpmax FAF is 4.75e-05 (0.00475%) and gnomAD v4.1 grpmax FAF is 9.28e-05 (0.00928%). Both are well below the 0.1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF = 4.75e-05 (0.00475%)
- gnomAD v4.1 grpmax FAF = 9.28e-05 (0.00928%)
- Both below BA1 threshold of 0.001 (0.1%)
Sources
BP4 BP4 per ENIGMA for silent variants applies only when the variant is inside a clinically important functional domain AND no splicing impact is predicted (SpliceAI ≤ 0.1). Val250 is outside both domains (PALB2: aa10-40, DNA binding: aa2481-3186). The BP4 rule for silent variants inside the domain is therefore not triggered. For missense variants outside the domain, BP4 is not applicable per the ENIGMA bioinformatic flowchart (Figure 1A). The synonymous variant at this position is better captured by BP1_Strong. Details ▾Hide ▴
Evidence considered
- V250 is outside clinically important functional domains
- SpliceAI delta = 0.00 (≤ 0.1)
- BP4 rule for silent variants only applies inside the domain
Sources
Not assessed · 9 · no assessment recorded
PS3 No well-established functional studies demonstrating a damaging effect were identified. The ENIGMA Specifications Table 9 (curated functional assay results) does not list c.750G>A. The variant is synonymous and SpliceAI predicts no splicing impact (max delta 0.00), making a pathogenic functional effect unlikely. None of the ClinVar-associated PMIDs (25741868, 26467025, 27495310, 28492532, 31843900) mention this specific variant in their full text. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 does not assign PS3 for this variant
- SpliceAI delta 0.00 confirms no predicted splicing impact
- No variant-specific functional data in reviewed publications
Still missing
- No calibrated functional assay data available for this synonymous variant
Sources
PS4 No case-control studies demonstrating enrichment of c.750G>A in affected individuals were identified. The variant is present in gnomAD population databases at low frequency, suggesting it does not exhibit strong case enrichment. The ENIGMA Supplementary Tables (ST7) do not list c.750G>A. None of the reviewed publications contained variant-specific case-control data. Details ▾Hide ▴
Evidence considered
- Present in gnomAD v2.1 at AF=3.9e-05 (11/282
- 244 alleles)
- Not in ENIGMA posterior probability reference set (ST7)
- No variant-specific case-control data in publications
Still missing
- No dedicated case-control study for this variant
Sources
PP1 No co-segregation data were identified for c.750G>A. The ENIGMA VCEP requires quantitative co-segregation analysis with LR ≥ 2.08 for PP1. No segregation studies mentioning this specific variant were found in the VCEP materials or reviewed publications. Details ▾Hide ▴
Evidence considered
- No variant-specific cosegregation data in VCEP materials or publications
Still missing
- No family segregation studies available for this variant
Sources
PP4 PP4 per ENIGMA requires a multifactorial likelihood ratio (LR ≥ 2.08) from calibrated clinical data. c.750G>A was not found in the Li et al. 2020 clinical-history LR table (PMID_31853058_BRCA2_clinical_history_LR.xlsx) or in the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001.xlsx). The variant is also absent from the ENIGMA ST7 Reference Set. Without calibrated LR data, PP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant not found in Li et al. 2020 clinical-history LR spreadsheet
- Variant not found in Parsons et al. 2019 multifactorial likelihood dataset
- Variant not found in ENIGMA ST7 Reference Set
Still missing
- No calibrated clinical-history LR available for this variant
Sources
BS2 BS2 per ENIGMA requires observation in the absence of Fanconi Anemia (FA) phenotype features, with a point system per proband (Specifications Table 8). No proband-level data with documented absence of FA features were identified for c.750G>A. While the variant is observed in gnomAD (suggesting healthy adult carriers), the ENIGMA BS2 pathway requires structured proband assessment that was not available. Details ▾Hide ▴
Evidence considered
- No proband-level BS2 assessment data available
- ENIGMA BS2 requires structured phenotype documentation (Specifications Table 8)
Still missing
- No proband data with FA phenotype absence documentation
Sources
BS3 BS3 per ENIGMA requires well-established functional studies showing no damaging effect, with code recommendations from calibrated published assays in Specifications Table 9. c.750G>A is not listed in ENIGMA Table 9. The exploratory evidence pass noted that Whiley et al. 2014 (PMID:24323938) reported normal splicing for c.750G>A, but this assay was not calibrated under the ENIGMA framework and the full text was not available for verification. Without VCEP-endorsed functional data, BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant not listed in ENIGMA Specifications Table 9 (curated functional assay results)
- No VCEP-endorsed BS3 functional data available
Still missing
- Whiley et al. 2014 (PMID:24323938) reported normal splicing but assay not calibrated under ENIGMA framework
- full text unavailable for confirmation
Sources
BS4 BS4 per ENIGMA requires quantitative co-segregation analysis showing lack of segregation (LR ≤ 0.48). No locus-specific segregation data for c.750G>A were found in the VCEP materials, ENIGMA ST7 Reference Set, or the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001). Details ▾Hide ▴
Evidence considered
- Variant not found in Parsons et al. 2019 multifactorial dataset
- Variant not found in ENIGMA ST7 Reference Set
- No variant-specific segregation data available
Still missing
- No family segregation studies available for this variant
Sources
cspec ↗vcep_humu_40_1557_s001
BP5 BP5 per ENIGMA requires a multifactorial likelihood ratio (LR ≤ 0.48) from calibrated clinical data. c.750G>A was not found in the Li et al. 2020 clinical-history LR table or the Parsons et al. 2019 multifactorial dataset. Without calibrated LR data in the benign direction, BP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant not found in clinical-history LR spreadsheet
- Variant not found in multifactorial likelihood dataset
Still missing
- No calibrated clinical-history LR available for this variant
Sources
BP7 BP7 per ENIGMA can be applied at Strong strength for silent variants with well-established mRNA assay data showing no damaging effect, or at Supporting strength for silent variants inside a clinically important domain if BP4 is met. c.750G>A is outside the domain, so the BP7_Supporting pathway does not apply. For BP7_Strong (RNA), a well-established mRNA functional assay is needed, but no VCEP-endorsed BP7 functional data are listed in Specifications Table 9 for this variant. While the exploratory evidence pass noted that Whiley et al. 2014 (PMID:24323938) reported normal splicing, this assay has not been calibrated under the ENIGMA framework and the full text was unavailable for independent verification. Details ▾Hide ▴
Evidence considered
- V250 outside clinically important domains — BP7_Supporting pathway not triggered
- No VCEP-endorsed mRNA assay data in Table 9
- SpliceAI delta 0.00 confirms no predicted splicing aberrancy
Still missing
- Whiley et al. 2014 (PMID:24323938) reported normal splicing but full text unavailable
- assay not calibrated under ENIGMA framework
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for synonymous (silent) variants. c.750G>A (p.Val250=) does not create a null variant (nonsense, frameshift, or canonical ±1,2 splice site) and no mRNA splicing disruption is predicted (SpliceAI max delta = 0.00). The variant is not in the ENIGMA PVS1/PM5_PTC exon decision table (Specifications Table 4). Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splicing impact (max delta 0.00)
- ENIGMA VCEP specification limits PVS1 to null variant types
- c.750G>A is a synonymous substitution (p.Val250=) in exon 9
Sources
PS1 N/APS1 requires a previously classified pathogenic variant with the same amino acid change or same predicted splicing impact. c.750G>A is synonymous (p.Val250=) and does not change the amino acid. No pathogenic comparator variant at this residue was identified. Details ▾Hide ▴
Evidence considered
- Synonymous variant does not change amino acid
- No known pathogenic comparator at Val250
Sources
PS2 VCEPPS2 is not applicable per ENIGMA VCEP. BRCA1/2-related cancers occur relatively commonly and de novo occurrences cannot be calibrated for predictive capacity. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable per ENIGMA VCEP. It is considered as a component of the bioinformatic analysis captured under PP3/BP4. Details ▾Hide ▴
Evidence considered
- ENIGMA VCEP states PM1 is captured by PP3/BP4 bioinformatic analysis
Sources
PM5 N/APM5 per ENIGMA is repurposed exclusively for protein termination codon (PTC) variants in exons where proven pathogenic PTCs exist (PM5_PTC). c.750G>A is a synonymous variant that does not create a termination codon. Additionally, PM5 candidate assessment confirmed no classic same-residue missense comparator pathway applies. Details ▾Hide ▴
Evidence considered
- ENIGMA PM5 is restricted to PTC variants (Specifications Table 4
- Appendix D)
- c.750G>A is synonymous
- not a PTC
- PM5 candidate search confirmed not applicable for this variant class
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not applicable per ENIGMA VCEP. BRCA1/2-related cancers occur relatively commonly and de novo occurrences cannot be calibrated for predictive capacity. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable per ENIGMA VCEP. The VCEP does not define PP2 as an applicable criterion for BRCA2. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable per ENIGMA VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable per ENIGMA VCEP. The VCEP does not define BP2 as an applicable criterion for BRCA2. Details ▾Hide ▴
BP3 VCEPBP3 (in-frame deletions/insertions in repetitive regions) is not applicable to this substitution variant, as specified in the skip list. Details ▾Hide ▴
Evidence considered
- c.750G>A is a single-nucleotide substitution
- not an in-frame indel
PS5 N/APS5 criterion (reputable source reports variant as pathogenic) is not present in the ENIGMA BRCA2 VCEP criteria set. The VCEP does not define a PS5 criterion. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.750G>A
- Protein (HGVS p.)
- NP_000050.3:p.(Val250=)
- GRCh38
- chr13:32330987 G>A
- GRCh37
- chr13:32905124 G>A
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
134 / 1,613,406 alleles
AF 8.31e-05 · 0 homozygotes · FAF 9.28e-05
gnomAD v2.1
11 / 282,244 alleles
AF 3.9e-05 · 0 homozygotes · FAF 4.75e-05
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 8.3e-05 · 134 / 1,613,406 alleles · 0 hom · FAF 9.3e-05
| Amish2 / 912 | 0.0022 |
| European (non-Finnish)128 / 1,179,546 | 0.00011 |
| Remaining individuals2 / 62,460 | 3.2e-05 |
| African/African American2 / 74,900 | 2.7e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,244 alleles · 0 hom · FAF 4.7e-05
| European (non-Finnish)10 / 128,766 | 7.8e-05 |
| African/African American1 / 24,916 | 4e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.30541e-05; MAF= 0.00831%, 134/1613406 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00219298; MAF= 0.21930%, 2/912 alleles, homozygotes = 0); grpmax FAF= 9.279e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89734e-05; MAF= 0.00390%, 11/282244 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76603e-05; MAF= 0.00777%, 10/128766 alleles, homozygotes = 0); grpmax FAF= 4.75e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 per ENIGMA 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 variant type regardless of location. c.750G>A is synonymous and located at Val250, which is outside both clinically important functional domains (PALB2 binding domain aa10-40 and DNA binding domain aa2481-3186). SpliceAI max delta score is 0.00, well below the 0.2 threshold. BayesDel score was not available. PP3 is not met under either pathway. Details ▾Hide ▴
Evidence considered
- V250 is outside BRCA2 clinically important functional domains (aa10-40
- aa2481-3186)
- SpliceAI max delta = 0.00 (< 0.2 threshold)
- No BayesDel score available
- REVEL also not found
Sources
BP4 BP4 per ENIGMA for silent variants applies only when the variant is inside a clinically important functional domain AND no splicing impact is predicted (SpliceAI ≤ 0.1). Val250 is outside both domains (PALB2: aa10-40, DNA binding: aa2481-3186). The BP4 rule for silent variants inside the domain is therefore not triggered. For missense variants outside the domain, BP4 is not applicable per the ENIGMA bioinformatic flowchart (Figure 1A). The synonymous variant at this position is better captured by BP1_Strong. Details ▾Hide ▴
Evidence considered
- V250 is outside clinically important functional domains
- SpliceAI delta = 0.00 (≤ 0.1)
- BP4 rule for silent variants only applies inside the domain
Sources
BP7 BP7 per ENIGMA can be applied at Strong strength for silent variants with well-established mRNA assay data showing no damaging effect, or at Supporting strength for silent variants inside a clinically important domain if BP4 is met. c.750G>A is outside the domain, so the BP7_Supporting pathway does not apply. For BP7_Strong (RNA), a well-established mRNA functional assay is needed, but no VCEP-endorsed BP7 functional data are listed in Specifications Table 9 for this variant. While the exploratory evidence pass noted that Whiley et al. 2014 (PMID:24323938) reported normal splicing, this assay has not been calibrated under the ENIGMA framework and the full text was unavailable for independent verification. Details ▾Hide ▴
Evidence considered
- V250 outside clinically important domains — BP7_Supporting pathway not triggered
- No VCEP-endorsed mRNA assay data in Table 9
- SpliceAI delta 0.00 confirms no predicted splicing aberrancy
Still missing
- Whiley et al. 2014 (PMID:24323938) reported normal splicing but full text unavailable
- assay not calibrated under ENIGMA framework
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
5 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
-
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.No paper-specific finding is recorded.
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
-
PMID 27495310 ↗Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.No paper-specific finding is recorded.
-
PMID 31843900 ↗Characterization of splice-altering mutations in inherited predisposition to cancer.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
134 / 1,613,406 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
10 Likely benign · 5 Benign · 1 Likely Benign · 1 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/?term=NM_000059.4%3Ac.750G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32905124-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32330987-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.750G…
- OncoKB ↗www.oncokb.org/gene/BRCA2/V250=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.750G%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
This variant is present in gnomAD v4.1 (AF= 8.30541e-05; MAF= 0.00831%, 134/1613406 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00219298; MAF= 0.21930%, 2/912 alleles, homozygotes = 0); grpmax FAF= 9.279e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89734e-05; MAF= 0.00390%, 11/282244 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76603e-05; MAF= 0.00777%, 10/128766 alleles, homozygotes = 0); grpmax FAF= 4.75e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (5 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 135814)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.