About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.1367T>C, p.(Ile456Thr)
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 BRCA1 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
ENIGMA BP1_Strong applies to missense variants located outside all (potentially) clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857) with no splicing predicted (SpliceAI ≤0.1). p.Ile456Thr is at position 456, outside all three domains. SpliceAI max delta = 0.00. Both conditions satisfied for BP1_Strong.
BP5Supporting
BP5 · supporting
ENIGMA BP5 captures combined likelihood ratio against pathogenicity from multifactorial likelihood clinical data. For NM_007294.4:c.1367T>C, the clinical-history LR from Li et al. 2020 (PMID:31853058) is 0.34 (LOG(LR) = −1.078, N=4 probands). This meets the BP5_Supporting threshold (LR ≤ 0.48). The Parsons et al. 2019 (PMID:31131967) combined multifactorial LR of 0.797 (co-occurrence LR=1.139, pathology LR=0.700) is directionally consistent with a benign interpretation but falls in the neutral zone for BP5. Only the Li 2020 clinical-history LR is used for code assignment per ENIGMA specifications.
Recorded classification: Likely benign
ENIGMA BRCA1/2 v1.2.0 Table 3 classification framework: 1 Strong Benign criterion (BP1_Strong) plus 1 Supporting Benign criterion (BP5_Supporting) satisfies the Likely Benign combination rule. No pathogenic criteria are met, so no point-system reconciliation is needed.
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
5 / 1,614,086 alleles
gnomAD v4.1: 5 / 1,614,086 alleles. Recorded AF 3.09773e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96654e-06; MAF= 0.00080%, 2/251050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.1546e-05; MAF= 0.00615%, 1/16248 alleles, homozygotes = 0).
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
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, conflicting classifications.
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. BRCA1, 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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58795217, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_007294.4:c.1367T>C (p.Ile456Thr) is a missense substitution in BRCA1 exon 10(11) at amino acid position 456, which lies outside the recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857).
BP1_Strong is met: the variant is a missense substitution outside all clinically important functional domains with no splicing predicted (SpliceAI max delta = 0.00), satisfying the ENIGMA v1.2.0 BP1_Strong rule.
BP5_Supporting is met: clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 0.34 (LOG(LR) = −1.078) based on 4 probands, meeting the BP5_Supporting threshold of LR ≤ 0.48.
The Parsons et al. 2019 (PMID:31131967) combined multifactorial analysis yielded a combined LR of 0.797 (moderate in favour of benign), directionally consistent with the Li 2020 clinical-history finding, though not independently meeting ENIGMA BP5 thresholds.
No pathogenic evidence criteria are met. The variant is present in gnomAD at extremely low frequency (v2.1: 2/251,050 alleles, AF=0.0008%; v4.1: 5/1,614,086 alleles) and is reported in ClinVar with conflicting classifications (Variation ID: 54222). No functional studies, case-control data, co-segregation data, or variant-specific literature were identified.
Under ENIGMA BRCA1 v1.2.0 Table 3 combination rules, 1 Strong Benign criterion (BP1_Strong) plus 1 Supporting Benign criterion (BP5_Supporting) meets the threshold for Likely Benign.
No criteria match.
Met · 2
BP1 StrongENIGMA BP1_Strong applies to missense variants located outside all (potentially) clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857) with no splicing predicted (SpliceAI ≤0.1). p.Ile456Thr is at position 456, outside all three domains. SpliceAI max delta = 0.00. Both conditions satisfied for BP1_Strong. Details ▾Hide ▴
Evidence considered
- Ile456 is outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains
- SpliceAI max delta = 0.00
- missense substitution.
Sources
BP5 SupportingENIGMA BP5 captures combined likelihood ratio against pathogenicity from multifactorial likelihood clinical data. For NM_007294.4:c.1367T>C, the clinical-history LR from Li et al. 2020 (PMID:31853058) is 0.34 (LOG(LR) = −1.078, N=4 probands). This meets the BP5_Supporting threshold (LR ≤ 0.48). The Parsons et al. 2019 (PMID:31131967) combined multifactorial LR of 0.797 (co-occurrence LR=1.139, pathology LR=0.700) is directionally consistent with a benign interpretation but falls in the neutral zone for BP5. Only the Li 2020 clinical-history LR is used for code assignment per ENIGMA specifications. Details ▾Hide ▴
Evidence considered
- Clinical history LR = 0.34 (Li 2020
- N=4 probands) meets BP5_Supporting threshold of ≤0.48
- Parsons 2019 combined LR = 0.797 is directionally concordant.
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No previously classified pathogenic or likely pathogenic variant resulting in the same amino acid change (Ile456Thr) or a different missense at codon 456 was identified in ClinVar or ENIGMA reference datasets. ENIGMA Table 9 and ST4 contain no functional or classificatory data for this codon. Details ▾Hide ▴
PS3 NM_007294.4:c.1367T>C (p.Ile456Thr) was not found in ENIGMA Specifications Table 9 (curated functional assay results) or Supplementary Table 4 (full functional assay dataset). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No variant-specific functional studies were identified in the literature. BRCA1 amino acid 456 lies outside the recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857) and is not within a domain characterized by systematic saturation mutagenesis or tiling screens. Details ▾Hide ▴
PS4 No case-control study with p-value ≤0.05 and OR ≥4 (lower CI excludes 2.0) was identified for this variant. The literature papers associated with this case are clinical practice guidelines (ACS, NSGC, USPSTF, ASCO), which do not provide variant-specific case-control data. The variant is present in gnomAD at extremely low frequency (AF=0.0008% in v2.1) but no case-control enrichment analysis is available. Details ▾Hide ▴
Evidence considered
- Literature review yielded only clinical practice guidelines with no variant-specific case-control data
- gnomAD frequency data alone insufficient for PS4.
Still missing
- No case-control study available for this variant.
Sources
PM2 ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome-only) and gnomAD v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 with 2 alleles (AF=7.97×10⁻⁶, 2/251,050 exomes) and in gnomAD v4.1 with 5 alleles (AF=3.10×10⁻⁶). Presence in population databases, even at extremely low frequency, precludes application of PM2_Supporting under ENIGMA rules. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/251
- 050 alleles (AF=0.0008%)
- gnomAD v4.1: 5/1
- 614
- 086 alleles (AF=0.00031%)
- variant is present
- not absent.
Sources
PP1 No co-segregation data are available for NM_007294.4:c.1367T>C. ENIGMA PP1 requires quantitative co-segregation analysis with likelihood ratio exceeding defined thresholds (LR≥2.08 for Supporting, ≥4.3 for Moderate, ≥18.7 for Strong). No such analysis was identified. Details ▾Hide ▴
Evidence considered
- No co-segregation analysis available for this variant.
Still missing
- No co-segregation data identified.
Sources
PP3 ENIGMA PP3 for missense variants requires the variant to be inside a clinically important functional domain (RING aa 2–101, coiled-coil aa 1391–1424, or BRCT aa 1650–1857) AND BayesDel no-AF score ≥0.28. p.Ile456Thr is at position 456, outside all three recognized domains. Additionally, SpliceAI max delta=0.00 (<0.2 threshold for splicing-based PP3) and BayesDel=0.122 (<0.28). None of the ENIGMA PP3 triggers are met. Details ▾Hide ▴
Evidence considered
- Position 456 outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains
- SpliceAI=0.00
- BayesDel=0.122
- REVEL=0.613 (informational only
- not used in ENIGMA PP3 rules).
Sources
PP4 ENIGMA PP4 uses the clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058). For NM_007294.4:c.1367T>C, LOG(LR) = −1.078, LR = 0.34 (N=4 probands). This falls in the benign direction, well below the PP4_Supporting threshold of LR≥2.08. The Parsons et al. 2019 (PMID:31131967) combined multifactorial LR = 0.797 also falls in the neutral-to-benign range, consistent with no pathogenic signal. Details ▾Hide ▴
Evidence considered
- Clinical history LR = 0.34 (Li 2020
- N=4 probands)
- combined multifactorial LR = 0.797 (Parsons 2019)
- both below PP4 thresholds and directionally benign.
Sources
BA1 ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% (>0.001) in gnomAD v2.1 (non-cancer, exome-only) and/or v3.1 (non-cancer) non-founder populations. gnomAD v2.1 AF = 7.97×10⁻⁶ (0.0008%); gnomAD v4.1 grpmax FAF = 6.8×10⁻⁷ (0.000068%). Both are orders of magnitude below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0008%
- v4.1 grpmax FAF=0.000068%
- both far below BA1 threshold of 0.1%.
Sources
BS1 ENIGMA BS1_Supporting requires FAF > 0.002% (>0.00002) and ≤0.01% in gnomAD non-cancer, non-founder populations. BS1_Strong requires FAF > 0.01% (>0.0001). gnomAD v2.1 AF = 0.0008% (below 0.002%); gnomAD v4.1 grpmax FAF = 0.000068% (below 0.002%). Both values fall below even the BS1_Supporting threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0008% < BS1_Supporting threshold of 0.002%
- v4.1 grpmax FAF=0.000068% < 0.002%.
Sources
BS2 ENIGMA BS2 requires evaluation using Specifications Table 8 points system based on observations in individuals without a Fanconi anemia phenotype. No proband-level observational data (age, phenotype, co-occurrence) are available for NM_007294.4:c.1367T>C to perform this points-based assessment. Details ▾Hide ▴
Evidence considered
- No proband-level data available for ENIGMA Table 8 points-based BS2 assessment.
Still missing
- No proband-specific observational data available.
Sources
BS3 NM_007294.4:c.1367T>C (p.Ile456Thr) was not found in ENIGMA Specifications Table 9 (curated functional assay results with pre-assigned BS3 strengths) or Supplementary Table 4 (full functional assay dataset). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No studies demonstrating no damaging effect on protein function were identified for this variant. Details ▾Hide ▴
BS4 No lack-of-segregation data are available for NM_007294.4:c.1367T>C. ENIGMA BS4 requires quantitative co-segregation analysis with likelihood ratio ≤0.48 (Supporting), ≤0.23 (Moderate), or ≤0.05 (Strong). No such analysis was identified. Details ▾Hide ▴
Evidence considered
- No co-segregation analysis available for this variant.
Still missing
- No segregation data identified.
Sources
BP4 ENIGMA BP4_Supporting for missense variants requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Although BayesDel (0.122) and SpliceAI (0.00) satisfy the in silico thresholds, p.Ile456Thr is at position 456, which lies outside all three recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857). The domain location requirement is not met. Details ▾Hide ▴
Evidence considered
- BayesDel=0.122 (≤0.15)
- SpliceAI=0.00 (≤0.1) — in silico thresholds met
- but variant at position 456 is outside RING
- coiled-coil
- and BRCT domains.
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established in vitro or in vivo functional studies showing no damaging effect on mRNA transcript profile. No mRNA splicing assay data were identified for NM_007294.4:c.1367T>C. The variant is not listed in ENIGMA Supplementary Table 3 (splicing references). ENIGMA BP7_Supporting applies only to silent variants inside clinically important domains (with BP4 met) or deep intronic variants, neither of which applies to this missense substitution. SpliceAI max delta = 0.00, consistent with no predicted splicing impact, but this alone does not trigger BP7 under ENIGMA rules. Details ▾Hide ▴
Evidence considered
- No mRNA assay data in ENIGMA ST3 or literature
- SpliceAI=0.00 confirms no predicted splicing impact but does not trigger BP7 for missense variants.
Still missing
- No mRNA transcript data available for this variant.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.1367T>C is a missense substitution (p.Ile456Thr), not a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). ENIGMA BRCA1 PVS1 is restricted to null variants. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 456 in BRCA1 exon 10(11)
- not a null variant type eligible for PVS1 under ENIGMA v1.2.0.
Sources
PS2 VCEPENIGMA BRCA1 v1.2.0 lists PS2 (de novo) as Not Applicable. Details ▾Hide ▴
Evidence considered
- Criterion marked Not Applicable by ClinGen ENIGMA BRCA1/2 Expert Panel.
Sources
PM1 VCEPENIGMA BRCA1 v1.2.0 lists PM1 as Not Applicable. Details ▾Hide ▴
Evidence considered
- Criterion marked Not Applicable by ClinGen ENIGMA BRCA1/2 Expert Panel.
Sources
PM5 N/AUnder ENIGMA BRCA1 v1.2.0, PM5 is repurposed exclusively for protein termination codon (PTC) variants (PM5_PTC), applied as additional weight for PTC variants already annotated with PVS1. NM_007294.4:c.1367T>C is a missense substitution, not a PTC variant. Classic same-residue-missense PM5 is not part of the ENIGMA framework for BRCA1. Details ▾Hide ▴
Evidence considered
- Missense variant at codon 456
- ENIGMA PM5 restricted to PTC variants
- pm5_candidates confirms mode=ptc_gene_specific
- eligible_for_classic_pm5_search=false.
Sources
PM6 VCEPENIGMA BRCA1 v1.2.0 lists PM6 (de novo, maternity/paternity not confirmed) as Not Applicable. Details ▾Hide ▴
Evidence considered
- Criterion marked Not Applicable by ClinGen ENIGMA BRCA1/2 Expert Panel.
Sources
PP2 VCEPENIGMA BRCA1 v1.2.0 lists PP2 (missense in gene with low rate of benign missense variation) as Not Applicable. Details ▾Hide ▴
Evidence considered
- Criterion marked Not Applicable by ClinGen ENIGMA BRCA1/2 Expert Panel.
Sources
PP5 VCEPENIGMA BRCA1 v1.2.0 lists PP5 (reputable source = pathogenic) as Not Applicable. ClinVar lists this variant with conflicting classifications (Variation ID: 54222) and review status 'criteria provided, conflicting classifications'; no expert panel submission exists. Details ▾Hide ▴
BP2 VCEPENIGMA BRCA1 v1.2.0 lists BP2 (observed in trans with pathogenic variant in recessive disorder) as Not Applicable. Details ▾Hide ▴
Evidence considered
- Criterion marked Not Applicable by ClinGen ENIGMA BRCA1/2 Expert Panel.
Sources
BP6 VCEPENIGMA BRCA1 v1.2.0 lists BP6 (reputable source = benign) as Not Applicable. Even if assessed under generic ACMG, ClinVar reports conflicting classifications with no expert panel consensus for this variant (Variation ID: 54222). Details ▾Hide ▴
PS5 N/APS5 (same amino acid change as established pathogenic variant regardless of nucleotide change) is not defined as a standalone criterion in the ENIGMA BRCA1 v1.2.0 specification; this scenario is captured by PS1 within the ENIGMA framework. Details ▾Hide ▴
Evidence considered
- PS5 not part of ENIGMA BRCA1/2 v1.2.0 criteria set
- functionally subsumed by PS1.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.1367T>C
- Protein (HGVS p.)
- NP_009225.1:p.(Ile456Thr)
- GRCh38
- chr17:43094164 A>G
- GRCh37
- chr17:41246181 A>G
- ClinVar
- 4856552, 4751061, 3386217, 3226103, 2819093, 868577, 824447, 629251, 628290, 54255
- COSMIC
- COSV58795217
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
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 BRCA1
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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
5 / 1,614,086 alleles
AF 3.1e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
2 / 251,050 alleles
AF 7.97e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,614,086 alleles · 0 hom · FAF 6.8e-07
| Remaining individuals1 / 62,500 | 1.6e-05 |
| African/African American1 / 75,050 | 1.3e-05 |
| European (non-Finnish)3 / 1,180,004 | 2.5e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 8e-06 · 2 / 251,050 alleles · 0 hom
| African/African American1 / 16,248 | 6.2e-05 |
| European (non-Finnish)1 / 113,456 | 8.8e-06 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.09773e-06; MAF= 0.00031%, 5/1614086 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6e-05; MAF= 0.00160%, 1/62500 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96654e-06; MAF= 0.00080%, 2/251050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.1546e-05; MAF= 0.00615%, 1/16248 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.613
- BayesDel
- 0.122
How the predictions were used
PP3 ENIGMA PP3 for missense variants requires the variant to be inside a clinically important functional domain (RING aa 2–101, coiled-coil aa 1391–1424, or BRCT aa 1650–1857) AND BayesDel no-AF score ≥0.28. p.Ile456Thr is at position 456, outside all three recognized domains. Additionally, SpliceAI max delta=0.00 (<0.2 threshold for splicing-based PP3) and BayesDel=0.122 (<0.28). None of the ENIGMA PP3 triggers are met. Details ▾Hide ▴
Evidence considered
- Position 456 outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains
- SpliceAI=0.00
- BayesDel=0.122
- REVEL=0.613 (informational only
- not used in ENIGMA PP3 rules).
Sources
BP4 ENIGMA BP4_Supporting for missense variants requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Although BayesDel (0.122) and SpliceAI (0.00) satisfy the in silico thresholds, p.Ile456Thr is at position 456, which lies outside all three recognized clinically important functional domains (RING aa 2–101, coiled-coil aa 1391–1424, BRCT aa 1650–1857). The domain location requirement is not met. Details ▾Hide ▴
Evidence considered
- BayesDel=0.122 (≤0.15)
- SpliceAI=0.00 (≤0.1) — in silico thresholds met
- but variant at position 456 is outside RING
- coiled-coil
- and BRCT domains.
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established in vitro or in vivo functional studies showing no damaging effect on mRNA transcript profile. No mRNA splicing assay data were identified for NM_007294.4:c.1367T>C. The variant is not listed in ENIGMA Supplementary Table 3 (splicing references). ENIGMA BP7_Supporting applies only to silent variants inside clinically important domains (with BP4 met) or deep intronic variants, neither of which applies to this missense substitution. SpliceAI max delta = 0.00, consistent with no predicted splicing impact, but this alone does not trigger BP7 under ENIGMA rules. Details ▾Hide ▴
Evidence considered
- No mRNA assay data in ENIGMA ST3 or literature
- SpliceAI=0.00 confirms no predicted splicing impact but does not trigger BP7 for missense variants.
Still missing
- No mRNA transcript data available for this variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.613. BayesDel score = 0.121631.
5 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 31853058 ↗Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio modelLi et al. 2020 (Genetics in Medicine) classified variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from a large multigene panel testing cohort. NM_007294.4:c.1367T>C (p.Ile456Thr) was assessed with a clinical-history LOG(LR) = −1.078 (LR = 0.34) based on 4 probands, indicating a benign-leaning personal/family-history profile.→ BP5 Names this variant
Source detail
LOG(LR) = −1.077894806861877; LR = 0.3403111928598089; N_Probands = 4
Location MOESM2 clinical history LR table (PMID_31853058_BRCA1_clinical_history_LR.xlsx); variant-level data extracted from supplementary material.
Other recorded publications
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society 2007 guidelines for breast screening with MRI as an adjunct to mammography. Discusses BRCA1/2 at the gene level in the context of breast cancer risk and screening recommendations. No variant-specific data.Does not name this variant
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PMID 23188549 ↗NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.National Society of Genetic Counselors 2012 practice guideline for risk assessment and genetic counseling for hereditary breast and ovarian cancer. Provides general recommendations for BRCA1/2 genetic testing and counseling. No variant-specific data.Does not name this variant
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.U.S. Preventive Services Task Force 2013 recommendation statement on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Provides population-level screening recommendations. No variant-specific data.Does not name this variant
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PMID 24366402 ↗Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.Patient summary of the USPSTF recommendations on genetic risk assessment for BRCA-related breast or ovarian cancer (companion to PMID:24366376). A consumer-facing summary with no variant-level data.Does not name this variant
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014American Society of Clinical Oncology 2014 expert statement on collection and use of cancer family history for oncology providers. Discusses BRCA1/2 at the gene level in the context of hereditary cancer risk assessment. No variant-specific data.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
5 / 1,614,086 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
Captured ClinVar source record
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/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_007294.4%3Ac.1367T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41246181-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43094164-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43094164-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.1367…
- OncoKB ↗www.oncokb.org/gene/BRCA1/I456T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=167902485
- 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= 3.09773e-06; MAF= 0.00031%, 5/1614086 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6e-05; MAF= 0.00160%, 1/62500 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96654e-06; MAF= 0.00080%, 2/251050 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.1546e-05; MAF= 0.00615%, 1/16248 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is present in ClinVar (Variation ID: 54222); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.613. BayesDel score = 0.121631.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, 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 previously been reported in somatic cancers (COSMIC; COSV58795217, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.