About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.241T>C, p.(Phe81Leu)
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
Absent from gnomAD v2.1 (non-cancer, exome subset) and gnomAD v4.1 in outbred populations. Per ENIGMA BRCA2 specifications, PM2 is applied at Supporting strength when absent from population databases. Coverage at this position appears adequate based on sister variant c.241T>G being observed (2 alleles in gnomAD v2.1).
Benign criteria applied · 1
BP1Strong
BP1 · strong
Missense variant (p.Phe81Leu) located outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI max delta score is 0.00 (≤0.10). Per ENIGMA BP1_Strong rule: missense variant outside a clinically important functional domain with no splicing predicted.
Recorded classification: Likely benign
Conflicting evidence: BP1_Strong (benign) and PM2_Supporting (pathogenic). ENIGMA BRCA2 VCEP conflicting-evidence point system applied: PM2_Supporting = +1, BP1_Strong = -4, total = -3. Range -6 to -2 = Likely Benign.
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
0.000 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
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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
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.
26 criteria with recorded statuses: 2 met · 6 not met · 6 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
BP1_Strong is met: the missense variant p.Phe81Leu (c.241T>C) lies outside both ENIGMA-defined clinically important functional domains (PALB2 binding domain aa 10-40 and DNA binding domain aa 2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00).
PM2_Supporting is met: the variant is absent from gnomAD v2.1 and v4.1 in outbred, non-cancer populations.
The sister variant c.241T>G (p.Phe81Val) is classified as Likely Benign by Parsons et al. 2019 multifactorial analysis (posterior probability 0.0066, IARC class 2), consistent with the BP1_Strong assignment for this position.
Katagiri et al. 1998 (PMID:9609997) observed c.241T>C in Family #32, a Japanese breast cancer family with 3 affected individuals (ages 35, 44, 58). The authors noted this was a novel missense alteration but did not perform segregation or functional analysis, and stated such analyses are needed to confirm pathogenicity.
No functional data (PS3/BS3), case-control data (PS4), clinical history LR (PP4/BP5), co-segregation data (PP1/BS4), or proband-level data (BS2) are available for this variant.
Under ENIGMA Table 3 combining rules: BP1_Strong (benign) and PM2_Supporting (pathogenic) are conflicting. Likely Benign requires 1 Strong Benign + 1 Supporting Benign; Likely Pathogenic requires substantially more pathogenic evidence. The evidence supports assignment as a Variant of Uncertain Significance (VUS) with conflicting evidence.
No criteria match.
Met · 2
PM2 SupportingAbsent from gnomAD v2.1 (non-cancer, exome subset) and gnomAD v4.1 in outbred populations. Per ENIGMA BRCA2 specifications, PM2 is applied at Supporting strength when absent from population databases. Coverage at this position appears adequate based on sister variant c.241T>G being observed (2 alleles in gnomAD v2.1). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome).
- Absent from gnomAD v4.1.
- Sister variant c.241T>G observed at 1.95e-05 in gnomAD v2.1 European (non-Finnish)
- confirming this position has adequate coverage.
Sources
BP1 StrongMissense variant (p.Phe81Leu) located outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI max delta score is 0.00 (≤0.10). Per ENIGMA BP1_Strong rule: missense variant outside a clinically important functional domain with no splicing predicted. Details ▾Hide ▴
Evidence considered
- Position 81 is outside PALB2 binding domain (aa 10-40) and DNA binding domain (aa 2481-3186).
- SpliceAI max delta = 0.00 (≤0.10).
- No predicted splicing impact.
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No known pathogenic or likely pathogenic missense variant at the same amino acid residue (p.Phe81) in BRCA2. The sister variant c.241T>G (p.Phe81Val) is classified as Likely Benign by Parsons 2019 multifactorial analysis (posterior probability 0.0066). SpliceAI max delta = 0.00, so no splicing concern for a PS1 splicing-based comparison. Details ▾Hide ▴
Evidence considered
- Sister variant c.241T>G (p.Phe81Val) is Likely Benign per Parsons 2019 (posterior 0.0066)
- not pathogenic. No pathogenic comparator at the same residue.
- SpliceAI max delta 0.00 confirms no splicing alteration.
Sources
PS3 Not present in ENIGMA Table 9 (curated PS3/BS3 functional assay assignments). Not found in the Dace & Findlay interim report. No variant-specific functional data identified in the literature. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- Not listed in ENIGMA Table 9 BRCA2 curated functional assay results.
- Not in Dace & Findlay saturation genome editing interim report.
- OncoKB classification: Unknown Oncogenic Effect.
Still missing
- No functional assay data available for p.Phe81Leu or a systematically characterized range that includes position 81.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
PP3 Position 81 is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186), so the domain-based PP3 rule (BayesDel ≥0.30 inside domain) does not apply. SpliceAI max delta score is 0.00, which is below the 0.20 threshold for the splicing-based PP3 rule. Neither PP3 condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (<0.20 threshold).
- BayesDel = 0.045 (<0.30 threshold).
- REVEL = 0.377.
- Position 81 outside functional domains (aa 10-40 and aa 2481-3186).
Sources
BA1 Filter allele frequency is below the ENIGMA BA1 threshold (FAF > 0.001, i.e., >0.1%). The variant is absent from gnomAD v2.1 and v4.1 in non-cancer, non-founder populations. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1. FAF does not exceed the 0.1% BA1 threshold.
Sources
BS1 Filter allele frequency is below both ENIGMA BS1 thresholds: BS1_Strong requires FAF > 0.01% (FAF > 0.0001) and BS1_Supporting requires FAF > 0.002% (FAF > 0.00002). The variant is absent from gnomAD v2.1 and v4.1. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1. FAF does not exceed BS1_Strong (0.01%) or BS1_Supporting (0.002%) thresholds.
Sources
BS3 Not present in ENIGMA Table 9 for BS3 assignments. No calibrated functional studies demonstrate a benign effect for this variant. The Katagiri 1998 paper contains no functional data. Details ▾Hide ▴
Evidence considered
- Not listed in ENIGMA Table 9 BRCA2 BS3 assignments.
- Not in Dace & Findlay interim report.
- No functional data in Katagiri 1998.
Still missing
- No functional assay data for this variant.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
Not assessed · 6 · no assessment recorded
PS4 No case-control data meeting ENIGMA thresholds (p≤0.05, OR≥4 with lower CI excluding 2.0) available for this variant. The single family observation in Katagiri et al. 1998 (1/78 Japanese breast cancer families) is an observational report, not a case-control study. Not present in the SupplementaryTables ST7 reference set posterior probability table. Details ▾Hide ▴
Evidence considered
- Katagiri 1998 (PMID:9609997): variant observed in 1/78 families
- not powered for case-control analysis.
Still missing
- No case-control study data available. No posterior probability in ENIGMA ST7 reference set.
PP1 No quantitative co-segregation analysis data available. Katagiri et al. 1998 (PMID:9609997) observed this variant in a family with 3 breast cancers (ages 35, 44, 58) but did not perform segregation analysis, and the authors explicitly stated that segregation analysis is needed to confirm pathogenicity. Does not meet ENIGMA PP1 LR thresholds (Supporting: LR≥2.08). Details ▾Hide ▴
Evidence considered
- Katagiri 1998 reports variant in Family #32 with 3 breast cancers but no co-segregation data collected.
Still missing
- No co-segregation likelihood ratio available.
PP4 c.241T>C was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical history likelihood ratio spreadsheet. Only the sister variant c.241T>G (LOG(LR) = -0.255, LR = 0.775, N=1) is present. No clinical-history LR data available to assess PP4. Details ▾Hide ▴
Evidence considered
- c.241T>C not found in Li et al. 2020 BRCA2 clinical history LR spreadsheet. Sister variant c.241T>G has LR=0.775 (neutral zone
- N=1).
Still missing
- No clinical-history likelihood ratio for c.241T>C.
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BS2 ENIGMA BS2 requires proband-level data with absence of Fanconi Anemia features for a point-based scoring system across multiple observations. No proband-level data are available in this case. Details ▾Hide ▴
Evidence considered
- No proband-level phenotypic data available for BS2 scoring.
Still missing
- No proband data to assess BS2 via ENIGMA Specifications Table 8 point system.
BS4 No quantitative lack-of-segregation data available. ENIGMA BS4 requires a co-segregation Bayes score with LR ≤0.48 (Supporting), ≤0.23 (Moderate), or ≤0.05 (Strong). No such data exist for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or lack-of-segregation data available.
Still missing
- No co-segregation likelihood ratio data.
BP5 c.241T>C was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical history likelihood ratio spreadsheet. Only the sister variant c.241T>G is present (LR = 0.775, neutral zone). No LR data against pathogenicity available. Details ▾Hide ▴
Evidence considered
- c.241T>C not found in Li et al. 2020 clinical history LR spreadsheet.
Still missing
- No clinical-history LR against pathogenicity for this variant.
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Phe81Leu); PVS1 requires a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion) or mRNA assay evidence (PVS1 RNA pathway). Neither applies. Details ▾Hide ▴
Evidence considered
- Missense substitution in exon 3
- not a null variant. No mRNA assay data available.
Sources
vcep_specifications_table4_v1_2_2024_11_18
PS2 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Details ▾Hide ▴
PM1 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Additionally, position 81 is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). Details ▾Hide ▴
Evidence considered
- CSPEC applicability rule: PM1 is Not Applicable for BRCA2.
- Position 81 is not within either recognized functional domain.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18
PM5 N/AENIGMA PM5 is repurposed for protein termination codon (PTC) variants in exons where proven pathogenic PTC variants exist. This is a missense variant (p.Phe81Leu), not a PTC. Per pm5_candidates.json, PM5 is in PTC/truncating logic mode and classic same-residue missense PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- PM5 repurposed for PTC variants only in BRCA2 ENIGMA framework.
- This variant is missense
- not a PTC.
- Exon 3 is PM5_PTC applicable but variant type does not qualify.
Sources
PM6 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Details ▾Hide ▴
PP2 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Details ▾Hide ▴
PP5 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Additionally, ClinVar classification is Uncertain significance with 1-star review status (criteria provided, single submitter), which would not meet the 3-star expert panel threshold for PP5 even under generic ACMG/AMP. Details ▾Hide ▴
BP2 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Details ▾Hide ▴
BP4 N/AENIGMA BP4 requires the variant to be inside a clinically important functional domain (PALB2 binding aa 10-40 or DNA binding aa 2481-3186) with no predicted impact (BayesDel ≤0.18 AND SpliceAI ≤0.10). Position 81 is outside both domains; BP4 is not applicable. Details ▾Hide ▴
Evidence considered
- Position 81 outside both functional domains. BP4 requires being inside a domain.
Sources
BP6 VCEPMarked Not Applicable by the ENIGMA BRCA2 VCEP (version 1.2.0). Details ▾Hide ▴
BP7 N/AENIGMA BP7 Strong (RNA) requires well-established mRNA assay evidence of no damaging effect. BP7 Supporting applies to silent variants inside domains (when BP4 is met) or intronic variants outside conserved splice positions (when BP4 is met). This is a missense variant with no RNA assay data; none of the BP7 pathways apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not silent
- not intronic
- no RNA assay data. SpliceAI max delta = 0.00.
Sources
PS5 N/ANot defined in the ENIGMA BRCA2 VCEP framework (version 1.2.0). The ClinVar classification is Uncertain significance with 1-star review status (single submitter). Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.241T>C
- Protein (HGVS p.)
- NP_000050.3:p.(Phe81Leu)
- GRCh38
- chr13:32319250 T>C
- GRCh37
- chr13:32893387 T>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…
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
- 0.377
- BayesDel
- 0.045
How the predictions were used
PP3 Position 81 is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186), so the domain-based PP3 rule (BayesDel ≥0.30 inside domain) does not apply. SpliceAI max delta score is 0.00, which is below the 0.20 threshold for the splicing-based PP3 rule. Neither PP3 condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (<0.20 threshold).
- BayesDel = 0.045 (<0.30 threshold).
- REVEL = 0.377.
- Position 81 outside functional domains (aa 10-40 and aa 2481-3186).
Sources
BP4 N/AENIGMA BP4 requires the variant to be inside a clinically important functional domain (PALB2 binding aa 10-40 or DNA binding aa 2481-3186) with no predicted impact (BayesDel ≤0.18 AND SpliceAI ≤0.10). Position 81 is outside both domains; BP4 is not applicable. Details ▾Hide ▴
Evidence considered
- Position 81 outside both functional domains. BP4 requires being inside a domain.
Sources
BP7 N/AENIGMA BP7 Strong (RNA) requires well-established mRNA assay evidence of no damaging effect. BP7 Supporting applies to silent variants inside domains (when BP4 is met) or intronic variants outside conserved splice positions (when BP4 is met). This is a missense variant with no RNA assay data; none of the BP7 pathways apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not silent
- not intronic
- no RNA assay data. SpliceAI max delta = 0.00.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.377. BayesDel score = 0.0452755.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
-
PMID 9609997 ↗High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families.BRCA2 c.241T>C (p.Phe81Leu) identified by PCR-SSCP in Family #32 among 78 unrelated Japanese breast cancer families. Three family members had breast cancer diagnosed at ages 35, 44, and 58. No segregation or functional analysis was performed. The authors concluded that such analyses are needed to confirm pathogenicity of the missense alterations reported.Names this variant
Quoted passage
Phe 81 Leu
Table 3 (page 46), Family #32; Results section, paragraph 2
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological background paper describing a variant classification framework. NM_000059.4:c.241T>C 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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
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/?term=NM_000059.4%3Ac.241T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32893387-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32319250-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32319250-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.241T…
- OncoKB ↗www.oncokb.org/gene/BRCA2/F81L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.241T%3EC
- 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 Uncertain significance (1 clinical laboratory). (ClinVarID = 51280)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.377. BayesDel score = 0.0452755.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.