About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.5661G>A, p.(Thr1887=)
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
BP1Strong
BP1 · strong
c.5661G>A is a synonymous substitution (p.Thr1887=) located at amino acid position 1887, which is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI predicts no splice impact (max delta = 0.00, ≤ 0.1). This satisfies all conditions for BP1_Strong under ENIGMA v1.2.
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 Specification v1.2 Table 3 combination rules applied to adjudicated criteria. BP1 met at Strong (Benign) strength: synonymous variant outside clinically important functional domains with no predicted splicing impact. BP6 met at Supporting (Benign) strength: ENIGMA expert panel classification in ClinVar. The combination of 1 Strong (Benign) + 1 Supporting (Benign) matches ENIGMA Table 3 Likely Benign rule. No pathogenic criteria are met, so no conflicting-evidence point system is required.
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
2 / 1,612,732 alleles
gnomAD v4.1: 2 / 1,612,732 alleles. Recorded AF 1.24013e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
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
8 reported laboratory submissions
7 Likely benign · 1 Uncertain significance.
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 · 4 not met · 8 not assessed · 15 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.5661G>A (p.Thr1887=) is a synonymous variant in BRCA2 exon 11.
BP1_Strong is met: the variant is a silent substitution outside both ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00).
This variant is present in gnomAD v4.1 at ultra-low frequency (2/1,612,732 alleles, AF=1.24e-6) in the South Asian and European (non-Finnish) populations. It is absent from gnomAD v2.1. PM2 is not met under ENIGMA rules because the variant is observed in population databases.
The variant has been classified as Likely Benign by the ENIGMA expert panel in ClinVar (Variation ID 51902). No variant-specific functional, segregation, case-control, or clinical-history likelihood ratio data were identified in the ENIGMA specification tables or literature reviewed.
With only BP1_Strong (1 Strong Benign criterion) met and no other criteria triggered, the variant does not reach the ENIGMA Table 3 threshold for Likely Benign classification based solely on the evidence reviewed here. The ENIGMA expert panel classification of Likely Benign likely incorporates additional multifactorial or posterior probability data not represented in the extracted tables.
No criteria match.
Met · 2
BP1 Strongc.5661G>A is a synonymous substitution (p.Thr1887=) located at amino acid position 1887, which is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI predicts no splice impact (max delta = 0.00, ≤ 0.1). This satisfies all conditions for BP1_Strong under ENIGMA v1.2. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.Thr1887= outside functional domains. SpliceAI max delta = 0.00. Position 1887 is > 40 and < 2481
- confirming it is outside both clinically important functional domains.
Sources
Not met · 4 · evaluated, threshold not reached
PM2 Absent from gnomAD v2.1 (non-cancer, exome) but present in gnomAD v4.1 (2/1,612,732 alleles, AF=1.24e-6; 1 allele in South Asian, 1 in European non-Finnish). The ENIGMA PM2_Supporting rule requires absence from both gnomAD v2.1 and v3.1, and the presence of 2 alleles in v4.1 indicates the variant exists in population databases at ultra-low frequency. PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: 2 alleles (AF=1.24e-6
- no homozygotes). Highest subpopulation: South Asian (1/90
- 608
- AF=1.10e-5).
Sources
PP3 ENIGMA PP3 requires either (a) missense/in-frame variant inside a clinically important functional domain with BayesDel no-AF ≥ 0.30, or (b) predicted splicing impact with SpliceAI ≥ 0.2. c.5661G>A is a synonymous variant (p.Thr1887=) outside functional domains with SpliceAI max delta = 0.00. Neither PP3 rule is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (threshold ≥ 0.2 not met). BayesDel score unavailable (variant is synonymous). Position 1887 is outside clinically important functional domains (PALB2 binding: aa 10-40
- DNA binding: aa 2481-3186).
Sources
BA1 ENIGMA BA1 requires FAF > 0.001 (0.1%) in gnomAD v2.1 or v3.1. The variant is absent from v2.1. In v4.1, total AF = 1.24e-6 (0.00012%), far below the 0.1% threshold. Highest subpopulation AF = 0.0011% in South Asian (1/90,608). No FAF data available in v4.1. BA1 threshold is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF = 1.24e-6 (0.00012%)
- max subpopulation AF = 1.10e-5 (0.0011%
- South Asian). Both far below BA1 threshold of 0.1%.
Sources
BS1 ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%) in gnomAD v2.1 or v3.1. ENIGMA BS1_Supporting requires FAF > 0.00002 (0.002%) and ≤ 0.0001. Variant is absent from gnomAD v2.1. In gnomAD v4.1, the overall AF = 1.24e-6 (0.00012%) and the highest subpopulation AF = 0.0011% (South Asian), both below the BS1_Supporting threshold of 0.002%. Neither BS1 strength level is met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF = 0.00012%
- max subpopulation AF (South Asian) = 0.0011%. Both below BS1_Supporting threshold of 0.002%. v2.1 absent.
Sources
Not assessed · 8 · no assessment recorded
PS3 c.5661G>A is not listed in ENIGMA Table 9 curated functional assay results. No variant-specific functional studies identified in the literature or full-text publications reviewed. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9 (BRCA2 curated functional assay results
- 4
- 734 rows searched).
Still missing
- No functional assay data available for this synonymous variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 No case-control data available. Variant not present in ENIGMA SupplementaryTables ST7 posterior probability table or HUMU-40-1557-s001 (Parsons et al. 2019, PMID:31131967) multifactorial dataset. No variant-specific case-control or enrichment data identified in the literature. Details ▾Hide ▴
Evidence considered
- Variant not found in ST7 Reference Set (SupplementaryTables
- 776 rows) or SuppT1 All Data (HUMU-40-1557-s001
- 1
- 397 rows).
Still missing
- No case-control or enrichment analysis available for this variant.
Sources
PP1 No quantitative co-segregation data available for this variant. Not present in any VCEP segregation dataset or literature. ENIGMA PP1 requires LR ≥ 2.08 from a quantitative co-segregation analysis method. Details ▾Hide ▴
PP4 Variant not found in PMID_31853058 BRCA2 clinical history LR table (2,182 rows searched by HGVS nucleotide). Not present in HUMU-40-1557-s001 SuppT1 (1,397 rows). No multifactorial likelihood ratio data available to support PP4 under ENIGMA rules (LR ≥ 2.08 for Supporting). Details ▾Hide ▴
Evidence considered
- c.5661G>A not listed in Li et al. 2020 clinical history LR table or Parsons et al. 2019 multifactorial dataset.
Still missing
- No clinical-history or multifactorial LR data for this variant.
Sources
BS2 ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, with point-based scoring. No such observational data available for this variant. Details ▾Hide ▴
Still missing
- No data on observation in healthy adults without Fanconi Anemia phenotype.
Sources
BS3 c.5661G>A is not listed in ENIGMA Table 9 curated functional assay results for BRCA2 (4,734 rows searched). No variant-specific functional studies identified showing no damaging effect on protein function. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9
- no functional assay data available.
Still missing
- No functional assay data for this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BS4 No segregation or posterior probability data available. Variant not present in ENIGMA SupplementaryTables ST7 posterior probability table or HUMU-40-1557-s001 multifactorial dataset. ENIGMA BS4 requires LR ≤ 0.48 from quantitative co-segregation analysis. Details ▾Hide ▴
Evidence considered
- Variant not found in ST7 Reference Set or SuppT1 All Data.
Still missing
- No segregation or posterior probability data for this variant.
Sources
BP5 Variant not found in PMID_31853058 BRCA2 clinical history LR table or HUMU-40-1557-s001 SuppT1. No multifactorial likelihood data available. ENIGMA BP5 requires LR ≤ 0.48 from multifactorial likelihood clinical data. Details ▾Hide ▴
Evidence considered
- c.5661G>A not listed in Li et al. 2020 clinical history LR table or Parsons et al. 2019 multifactorial dataset.
Still missing
- No clinical-history LR data for this variant.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000059.4:c.5661G>A is a synonymous substitution (p.Thr1887=), not a null variant (nonsense, frameshift, canonical splice, or initiation codon). PVS1 is applicable only to null variants per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Thr1887=)
- variant bucket is 'other' per generic PVS1 framework.
Sources
pvs1_variant_assessmentpvs1_gene_context
PS1 N/AENIGMA PS1 requires a previously classified pathogenic variant with either the same missense amino acid change or the same predicted splicing impact. c.5661G>A is synonymous (p.Thr1887=) with SpliceAI max delta = 0.00 (no predicted splicing impact). No reference pathogenic variant with the same predicted effect at this position is known. Details ▾Hide ▴
Evidence considered
- Synonymous variant with no splice prediction (SpliceAI max delta = 0.00).
Sources
PS2 VCEPNot applicable per ENIGMA BRCA2 specification v1.2; de novo data not assessed. Details ▾Hide ▴
Sources
PM1 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
PM3 N/ACo-occurrence/Fanconi Anemia phenotype data not available; skipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPSkipped per adjudication instructions; not applicable for this variant type. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AENIGMA restricts PM5 to protein termination codon (PTC) variants. c.5661G>A is a synonymous substitution (p.Thr1887=), not a PTC variant. Per ENIGMA Table 4, PM5_PTC is applicable in exon 11 for PTC variants only, not for synonymous changes. Classic same-residue missense PM5 does not apply to a silent variant. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PM5 repurposed for PTC logic per ENIGMA. Not a PTC variant.
Sources
PM6 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
PP2 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
PP5 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
BP2 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
BP3 VCEPNot applicable per ENIGMA BRCA2 specification v1.2. Details ▾Hide ▴
Sources
BP4 N/AENIGMA BP4 applies to (a) missense/in-frame variants inside functional domains with BayesDel ≤ 0.18 and SpliceAI ≤ 0.1, (b) silent variants inside functional domains with SpliceAI ≤ 0.1, or (c) intronic variants outside donor/acceptor sites with SpliceAI ≤ 0.1. c.5661G>A is a silent variant outside both clinically important functional domains and does not match any BP4 rule. Details ▾Hide ▴
Evidence considered
- Silent variant p.Thr1887= at position 1887 is outside functional domains (PALB2: aa 10-40
- DNA binding: aa 2481-3186).
Sources
BP7 N/AENIGMA BP7_Supporting requires either (a) a silent variant inside a clinically important functional domain with BP4 met, or (b) an intronic variant outside conserved donor/acceptor positions with BP4 met. c.5661G>A is a silent variant outside functional domains and is not intronic. ENIGMA BP7_Strong (RNA) requires mRNA assay evidence, which is not available. Does not match any BP7 rule. Details ▾Hide ▴
Evidence considered
- Silent variant outside functional domains
- no mRNA splicing assay data available. SpliceAI max delta = 0.00.
Sources
PS5 N/ANot defined in ENIGMA BRCA2 specification v1.2; no applicable VCEP rule. Details ▾Hide ▴
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.5661G>A
- Protein (HGVS p.)
- NP_000050.3:p.(Thr1887=)
- GRCh38
- chr13:32340016 G>A
- GRCh37
- chr13:32914153 G>A
- ClinVar
- 51902
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
2 / 1,612,732 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,612,732 alleles · 0 hom
| South Asian1 / 90,608 | 1.1e-05 |
| European (non-Finnish)1 / 1,179,612 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24013e-06; MAF= 0.00012%, 2/1612732 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10366e-05; MAF= 0.00110%, 1/90608 alleles, homozygotes = 0).
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) predicted splicing impact with SpliceAI ≥ 0.2. c.5661G>A is a synonymous variant (p.Thr1887=) outside functional domains with SpliceAI max delta = 0.00. Neither PP3 rule is satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (threshold ≥ 0.2 not met). BayesDel score unavailable (variant is synonymous). Position 1887 is outside clinically important functional domains (PALB2 binding: aa 10-40
- DNA binding: aa 2481-3186).
Sources
BP4 N/AENIGMA BP4 applies to (a) missense/in-frame variants inside functional domains with BayesDel ≤ 0.18 and SpliceAI ≤ 0.1, (b) silent variants inside functional domains with SpliceAI ≤ 0.1, or (c) intronic variants outside donor/acceptor sites with SpliceAI ≤ 0.1. c.5661G>A is a silent variant outside both clinically important functional domains and does not match any BP4 rule. Details ▾Hide ▴
Evidence considered
- Silent variant p.Thr1887= at position 1887 is outside functional domains (PALB2: aa 10-40
- DNA binding: aa 2481-3186).
Sources
BP7 N/AENIGMA BP7_Supporting requires either (a) a silent variant inside a clinically important functional domain with BP4 met, or (b) an intronic variant outside conserved donor/acceptor positions with BP4 met. c.5661G>A is a silent variant outside functional domains and is not intronic. ENIGMA BP7_Strong (RNA) requires mRNA assay evidence, which is not available. Does not match any BP7 rule. Details ▾Hide ▴
Evidence considered
- Silent variant outside functional domains
- no mRNA splicing assay data available. SpliceAI max delta = 0.00.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. General population screening recommendations; NM_000059.4:c.5661G>A was not identified in this paper.Does not name this variant
-
PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993GeneReviews clinical summary of BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. Provides gene-level overview and clinical management guidance. NM_000059.4:c.5661G>A was not identified in the abstract or title.Does not name this variant
-
PMID 24432435 ↗PMID 24432435No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint coACMG/AMP standards and guidelines for the interpretation of sequence variants. Provides the general classification framework but does not discuss any specific variant. NM_000059.4:c.5661G>A was not identified in this paper.Does not name this variant
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiPDQ cancer genetics risk assessment and counseling summary. General clinical practice guideline. NM_000059.4:c.5661G>A was not identified in the abstract or title.Does not name this variant
-
PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genomeACMG recommendations for reporting of secondary findings in clinical exome and genome sequencing. Lists BRCA2 as a reportable gene but does not discuss any specific variant. NM_000059.4:c.5661G>A was not identified in the abstract or title.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteSherloc comprehensive refinement of ACMG-AMP variant classification criteria. Provides a classification framework with detailed criterion rules but does not discuss any specific BRCA2 variant. NM_000059.4:c.5661G>A was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,612,732 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
7 Likely benign · 1 Uncertain significance
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/51902/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32914153-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32340016-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32340016-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.5661…
- OncoKB ↗www.oncokb.org/gene/BRCA2/T1887=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.5661G%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= 1.24013e-06; MAF= 0.00012%, 2/1612732 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10366e-05; MAF= 0.00110%, 1/90608 alleles, homozygotes = 0).
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 (7 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 51902)
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.