About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.19C>T, p.(Arg7Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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. 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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BS1Supporting
BS1 · supporting
ENIGMA BS1_Supporting requires FAF > 0.002% (FAF > 0.00002) and ≤ 0.01% (≤ 0.0001). The gnomAD v2.1 grpmax FAF is 2.299e-05, which marginally exceeds the 0.00002 supporting threshold. However, gnomAD v4.1 grpmax FAF is 1.884e-05, which falls below the same threshold. Given the borderline nature and discrepancy between gnomAD versions, this call warrants human review. The variant has been observed in 6 alleles (v2.1) and 35 alleles (v4.1) with no homozygotes.
Recorded classification: Uncertain significance
Only one criterion met: BS1 at supporting benign strength (gnomAD v2.1 grpmax FAF 2.299e-05 marginally above the 0.00002 threshold, though v4.1 FAF 1.884e-05 falls below). ENIGMA Table 3 requires a minimum of 2 Supporting (Benign) or 1 Strong (Benign) + 1 Supporting (Benign) for Likely Benign. The ENIGMA point-based scoring system assigns -1 point, which falls in the VUS range (-1 to 5). No pathogenic criteria are met. The single borderline BS1_Supporting call is insufficient to reach any classification other than VUS.
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
35 / 1,613,308 alleles
gnomAD v4.1: 35 / 1,613,308 alleles. Recorded AF 2.16946e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.38992e-05; MAF= 0.00239%, 6/251054 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2925e-05; MAF= 0.00529%, 6/113368 alleles, homozygotes = 0); grpmax FAF= 2.299e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.170 maximum delta
Recorded SpliceAI maximum delta score: 0.170. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
15 reported laboratory submissions
11 Likely benign · 3 Uncertain significance · 1 Likely Benign. 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV100524047, n = 2 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, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 15 not met · 0 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
NM_007294.4:c.19C>T (p.Arg7Cys) is a missense variant in exon 2 of BRCA1, within the RING domain (aa 2-101).
This variant is present at very low frequency in population databases: gnomAD v2.1 (6/251054 alleles, AF=2.39e-05) and gnomAD v4.1 (35/1613308 alleles, AF=2.17e-05), with no homozygotes observed.
The variant has been reported in ClinVar as Likely benign by 11 clinical laboratories and as Uncertain significance by 3 laboratories (ClinVar Variation ID: 37440, review status: criteria provided, single submitter).
ENIGMA Table9 classifies c.19C>T as 'None' (N/A) for both PS3 and BS3 due to discordant functional results: Findlay 2018 (PMID:30209399) reported no functional impact via saturation genome editing, while Bouwman 2020 (PMID:32546644) reported a deleterious effect via HRR complementation assay.
BayesDel no-AF score (0.021) falls below the PP3 threshold (≥0.28) and within the BP4 benign prediction range (≤0.15), but SpliceAI max delta (0.17) exceeds the BP4 threshold (≤0.1), precluding both PP3 and BP4 application under ENIGMA rules.
The Parsons et al. 2019 multifactorial likelihood analysis yielded a combined LR of 1.1146 (neutral zone), providing insufficient evidence for either PP4 or BP5.
The gnomAD v2.1 grpmax FAF of 2.299e-05 marginally exceeds the ENIGMA BS1_Supporting threshold (FAF > 0.00002), but the gnomAD v4.1 FAF of 1.884e-05 falls below this threshold. This borderline frequency evidence was applied as BS1_Supporting with a recommendation for human review.
No pathogenic evidence criteria are met. PVS1, PS1-PS5, PM1, PM2, PM5, PM6, PP1-PP5 are all not met or not applicable. The only criterion met is BS1 at supporting benign strength.
No criteria match.
Met · 1
BS1 SupportingENIGMA BS1_Supporting requires FAF > 0.002% (FAF > 0.00002) and ≤ 0.01% (≤ 0.0001). The gnomAD v2.1 grpmax FAF is 2.299e-05, which marginally exceeds the 0.00002 supporting threshold. However, gnomAD v4.1 grpmax FAF is 1.884e-05, which falls below the same threshold. Given the borderline nature and discrepancy between gnomAD versions, this call warrants human review. The variant has been observed in 6 alleles (v2.1) and 35 alleles (v4.1) with no homozygotes. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF: 2.299e-05 — above BS1_Supporting threshold of 0.00002.
- gnomAD v4.1 grpmax FAF: 1.884e-05 — below BS1_Supporting threshold.
- 6/251054 alleles (v2.1)
- 35/1613308 alleles (v4.1)
- 0 homozygotes.
Still missing
- Borderline FAF call: v2.1 just above threshold
- v4.1 below threshold. ENIGMA Appendix G review recommended.
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No previously classified pathogenic missense variant exists at amino acid position 7 (Arg7) to serve as a PS1 comparator. All sister variants at this position are classified as benign (BS3 per ENIGMA Table9: c.19C>G/p.Arg7Gly, c.20G>A/p.Arg7His, c.20G>C/p.Arg7Pro, c.20G>T/p.Arg7Leu) or indeterminate (c.19C>A/p.Arg7Ser, code None). Details ▾Hide ▴
Evidence considered
- ENIGMA Table9 confirms no pathogenic classification for any Arg7 missense variant
- all are BS3 or None.
Sources
vcep_specifications_table9_v1_2_2024_11_18
PS3 ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T. Two calibrated functional studies produced discordant results: Findlay 2018 (PMID:30209399) classified the variant as functionally normal (FUNC), while Bouwman 2020 (PMID:32546644) classified it as deleterious. Per ENIGMA specification, discordant results from well-established assays preclude application of PS3. Details ▾Hide ▴
Evidence considered
- Findlay 2018 (PMID:30209399): saturation genome editing assay — c.19C>T classified as FUNC (no functional impact).
- Bouwman 2020 (PMID:32546644): HRR complementation assay — c.19C>T classified as Deleterious.
- ENIGMA Table9 curation confirms discordant results
- PS3 and BS3 not met.
Still missing
- Resolution of discordant functional data between Findlay 2018 and Bouwman 2020 would be needed to determine functional impact.
Sources
vcep_specifications_table9_v1_2_2024_11_18PMID:32546644 ↗
PS4 No case-control study demonstrates significantly increased prevalence of c.19C>T in affected individuals compared to controls. The ENIGMA PS4 threshold requires p≤0.05 and OR≥4 with lower confidence interval excluding 2.0. No such data are available in the case materials. Details ▾Hide ▴
Evidence considered
- No case-control data available in case materials or ENIGMA specification.
Still missing
- Case-control study data would be required to meet PS4.
PM2 ENIGMA PM2_Supporting requires the variant to be absent from controls in gnomAD v2.1 and v3.1. NM_007294.4:c.19C>T is present in gnomAD v2.1 (6/251054 alleles, AF=2.39e-05) and gnomAD v4.1 (35/1613308 alleles, AF=2.17e-05). Presence in population databases precludes PM2 application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 6/251054 alleles (AF=2.39e-05)
- 0 homozygotes.
- gnomAD v4.1: 35/1613308 alleles (AF=2.17e-05)
Sources
PP1 No co-segregation data are available for NM_007294.4:c.19C>T. ENIGMA PP1 requires quantitative co-segregation analysis with LR≥2.08 for supporting, ≥4.3 for moderate, ≥18.7 for strong. No family studies or co-segregation LRs are present in the case materials. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- Co-segregation analysis in affected families would be needed to evaluate PP1.
PP3 The variant lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain. However, ENIGMA PP3 requires BayesDel no-AF score ≥0.28 for protein impact prediction, and SpliceAI ≥0.2 for splicing prediction. BayesDel for c.19C>T is 0.021 (far below 0.28 threshold). SpliceAI max delta is 0.17 (below 0.2 threshold). Neither bioinformatic threshold for PP3 is met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score: 0.021 — well below PP3 threshold of ≥0.28.
- SpliceAI max delta: 0.17 — below PP3 splicing threshold of ≥0.2.
- REVEL score: 0.558 (not used by ENIGMA
- BayesDel is the specified predictor).
Sources
PP4 The ENIGMA PP4 criterion captures combined multifactorial likelihood ratios toward pathogenicity. From the Parsons et al. 2019 (PMID:31131967) multifactorial analysis, c.19C>T has a combined LR of 1.1146, which falls in the neutral zone (>0.48 and <2.08) and does not meet the PP4_Supporting threshold of LR≥2.08. The variant was not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table. No other multifactorial data support pathogenicity. Details ▾Hide ▴
Evidence considered
- Parsons 2019 (PMID:31131967): Combined LR = 1.1146
- IARC class undetermined (neutral zone).
- Li 2020 (PMID:31853058): c.19C>T not present in clinical-history LR table
- no variant-specific clinical LR available.
Still missing
- Additional proband family history data could allow clinical-history LR calculation.
Sources
vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lr
BA1 ENIGMA BA1 (Stand Alone benign) requires a filter allele frequency (FAF) above 0.1% (FAF > 0.001). The maximum grpmax FAF for c.19C>T is 2.299e-05 (gnomAD v2.1) and 1.884e-05 (gnomAD v4.1), both several orders of magnitude below the 0.001 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF: 2.299e-05 (European Non-Finnish).
- gnomAD v4.1 grpmax FAF: 1.884e-05 (Middle Eastern).
- Both well below BA1 threshold of 0.001.
Sources
BS2 ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, scored using the points system in ENIGMA Table 8. No proband-level data are available in the case materials to calculate BS2 points. Details ▾Hide ▴
Evidence considered
- No proband observation data available for BS2 point calculation.
Still missing
- Observation data in healthy adults would be needed to calculate BS2 points per ENIGMA Table 8.
BS3 ENIGMA Table9 assigns code 'None' (N/A) for c.19C>T. Two calibrated functional studies produced discordant results: Findlay 2018 (PMID:30209399) classified the variant as functionally normal (FUNC), while Bouwman 2020 (PMID:32546644) classified it as deleterious. Per ENIGMA specification, discordant results from well-established assays preclude application of BS3. Details ▾Hide ▴
Evidence considered
- Findlay 2018 (PMID:30209399): saturation genome editing — c.19C>T classified as FUNC.
- Bouwman 2020 (PMID:32546644): HRR complementation — c.19C>T classified as Deleterious.
- ENIGMA Table9: code None — discordant results preclude BS3.
Still missing
- Resolution of discordant functional data would be needed to determine functional impact.
Sources
vcep_specifications_table9_v1_2_2024_11_18PMID:32546644 ↗
BS4 ENIGMA BS4 requires lack of segregation in affected family members as measured by a quantitative co-segregation analysis method. No segregation data or likelihood ratios are available for c.19C>T. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- Segregation analysis in affected families would be needed to evaluate BS4.
BP1 ENIGMA BP1_Strong applies to missense variants located OUTSIDE a clinically important functional domain AND with no splicing predicted (SpliceAI ≤0.1). c.19C>T (p.Arg7Cys) lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain. The variant does not qualify for BP1. Details ▾Hide ▴
Evidence considered
- RING domain (aa 2-101) is a clinically important functional domain per ENIGMA
- variant is inside domain
- excluding BP1.
Sources
BP4 ENIGMA BP4_Supporting requires: inside a clinically important functional domain AND BayesDel ≤0.15 AND SpliceAI ≤0.1. c.19C>T is in the RING domain (qualifies) and BayesDel = 0.021 (≤0.15, qualifies), but SpliceAI max delta = 0.17 (>0.1, does not qualify). The SpliceAI score exceeds the BP4 threshold, precluding BP4 application. Details ▾Hide ▴
Evidence considered
- RING domain (aa 2-101): qualifies as clinically important functional domain.
- BayesDel no-AF: 0.021 — ≤0.15 threshold met.
- SpliceAI max delta: 0.17 — exceeds ≤0.1 threshold
- BP4 not met.
Sources
bayesdelspliceai ↗
BP5 ENIGMA BP5 captures combined multifactorial likelihood ratios against pathogenicity. From Parsons et al. 2019 (PMID:31131967), the combined LR for c.19C>T is 1.1146, falling in the neutral zone (>0.48 and <2.08). This does not meet the BP5_Supporting threshold of LR≤0.48. The variant was not present in the Li et al. 2020 clinical-history LR table. Details ▾Hide ▴
Evidence considered
- Parsons 2019 (PMID:31131967): Combined LR = 1.1146 (neutral zone).
- Li 2020 (PMID:31853058): variant not found in clinical-history LR table.
Still missing
- Additional proband data could allow clinical-history LR calculation.
Sources
vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lr
PS5 No previously classified pathogenic variant exists at amino acid position 7 (Arg7) with a different missense change. All sister missense variants at this position are classified as benign (BS3) or indeterminate (None) in ENIGMA Table9. Details ▾Hide ▴
Evidence considered
- ENIGMA Table9: c.19C>G (R7G) = BS3
- c.20G>A (R7H) = BS3
- c.20G>C (R7P) = BS3
- c.20G>T (R7L) = BS3
- c.19C>A (R7S) = None. No pathogenic comparator at position 7.
Sources
vcep_specifications_table9_v1_2_2024_11_18
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.19C>T is a missense variant (p.Arg7Cys). PVS1 under the ENIGMA BRCA1 specification is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, single or multi-exon deletion). This missense substitution does not qualify. Details ▾Hide ▴
Evidence considered
- Missense substitution (Arg7Cys)
- not a null variant type eligible for PVS1 under ENIGMA v1.2.
Sources
pvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18
PS2 VCEPPS2/PM6 de novo criteria are not applicable for BRCA1 under the ENIGMA v1.2 specification. BRCA1/2-related cancers occur relatively commonly; no information is available to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC explicitly marks PS2 applicability as Not Applicable.
Sources
PM1 VCEPPM1 is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC states PM1 is 'considered as component of bioinformatic analysis (PP3/BP4)' rather than applied independently. The variant's location in the RING domain (aa 2-101) is captured by PP3/BP4 bioinformatic assessment. Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC explicitly marks PM1 applicability as Not Applicable
- absorbed into PP3/BP4 framework.
Sources
PM5 N/AENIGMA repurposes PM5 specifically for protein termination codon (PTC) variants, as a complement to PVS1. NM_007294.4:c.19C>T is a missense variant (p.Arg7Cys), not a PTC. The pm5_candidates.json confirms classic same-residue missense PM5 is not applicable under this framework. Details ▾Hide ▴
Evidence considered
- Missense variant
- PM5 is restricted to PTC variants under ENIGMA v1.2.
Sources
pm5_candidatesvcep_specifications_table4_v1_2_2024_11_18
PM6 VCEPPM6 de novo criteria are not applicable for BRCA1 under the ENIGMA v1.2 specification. BRCA1/2-related cancers occur relatively commonly; insufficient information exists to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC explicitly marks PM6 applicability as Not Applicable.
Sources
PP2 VCEPPP2 (missense variant in a gene with low rate of benign missense variation) is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC marks PP2 applicability as Not Applicable. Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC explicitly marks PP2 applicability as Not Applicable.
Sources
PP5 VCEPPP5 is explicitly marked 'Not Applicable for this VCEP' by the ENIGMA BRCA1 specification v1.2. Furthermore, the ClinVar review status for this variant is 'criteria provided, single submitter' (1-star), which does not meet the global 3-star expert panel threshold for PP5 application. Details ▾Hide ▴
BP2 VCEPBP2 (observed in trans with a pathogenic variant for a fully penetrant dominant disorder) is not applicable under the ENIGMA BRCA1 v1.2 specification. The CSPEC marks BP2 applicability as Not Applicable. Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC explicitly marks BP2 applicability as Not Applicable.
Sources
BP3 VCEPBP3 (in-frame deletion/insertion in a repetitive region without known function) is not applicable for a missense substitution variant. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 applies only to in-frame indels in repetitive regions.
BP6 VCEPBP6 is explicitly marked 'Not Applicable for this VCEP' by the ENIGMA BRCA1 specification v1.2. The ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the global 3-star expert panel threshold for BP6 application. Details ▾Hide ▴
BP7 N/AENIGMA BP7 applies to silent/intronic variants for splicing data, or to missense variants outside clinically important functional domains for RNA assay data. c.19C>T is a missense variant inside the RING domain (aa 2-101). For missense variants inside a functional domain, BS3 must be met for BP7_Strong(RNA) eligibility, which is not satisfied. BP7_Supporting is restricted to silent/intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant inside RING domain
- BS3 not met
- BP7 not applicable for this variant type.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.19C>T
- Protein (HGVS p.)
- NP_009225.1:p.(Arg7Cys)
- GRCh38
- chr17:43124078 G>A
- GRCh37
- chr17:41276095 G>A
- ClinVar
- 54307, 37440
- COSMIC
- COSV100524047
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
35 / 1,613,308 alleles
AF 2.17e-05 · 0 homozygotes · FAF 1.88e-05
gnomAD v2.1
6 / 251,054 alleles
AF 2.39e-05 · 0 homozygotes · FAF 2.3e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.2e-05 · 35 / 1,613,308 alleles · 0 hom · FAF 1.9e-05
| Middle Eastern1 / 6,074 | 0.00016 |
| European (non-Finnish)31 / 1,179,452 | 2.6e-05 |
| East Asian1 / 44,850 | 2.2e-05 |
| Remaining individuals1 / 62,452 | 1.6e-05 |
| South Asian1 / 91,076 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), Amish, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2.4e-05 · 6 / 251,054 alleles · 0 hom · FAF 2.3e-05
| European (non-Finnish)6 / 113,368 | 5.3e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, 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= 2.16946e-05; MAF= 0.00217%, 35/1613308 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 1.884e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.38992e-05; MAF= 0.00239%, 6/251054 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2925e-05; MAF= 0.00529%, 6/113368 alleles, homozygotes = 0); grpmax FAF= 2.299e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.558
- BayesDel
- 0.021
How the predictions were used
PP3 The variant lies within the BRCA1 RING domain (aa 2-101), a clinically important functional domain. However, ENIGMA PP3 requires BayesDel no-AF score ≥0.28 for protein impact prediction, and SpliceAI ≥0.2 for splicing prediction. BayesDel for c.19C>T is 0.021 (far below 0.28 threshold). SpliceAI max delta is 0.17 (below 0.2 threshold). Neither bioinformatic threshold for PP3 is met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score: 0.021 — well below PP3 threshold of ≥0.28.
- SpliceAI max delta: 0.17 — below PP3 splicing threshold of ≥0.2.
- REVEL score: 0.558 (not used by ENIGMA
- BayesDel is the specified predictor).
Sources
BP4 ENIGMA BP4_Supporting requires: inside a clinically important functional domain AND BayesDel ≤0.15 AND SpliceAI ≤0.1. c.19C>T is in the RING domain (qualifies) and BayesDel = 0.021 (≤0.15, qualifies), but SpliceAI max delta = 0.17 (>0.1, does not qualify). The SpliceAI score exceeds the BP4 threshold, precluding BP4 application. Details ▾Hide ▴
Evidence considered
- RING domain (aa 2-101): qualifies as clinically important functional domain.
- BayesDel no-AF: 0.021 — ≤0.15 threshold met.
- SpliceAI max delta: 0.17 — exceeds ≤0.1 threshold
- BP4 not met.
Sources
bayesdelspliceai ↗
BP7 N/AENIGMA BP7 applies to silent/intronic variants for splicing data, or to missense variants outside clinically important functional domains for RNA assay data. c.19C>T is a missense variant inside the RING domain (aa 2-101). For missense variants inside a functional domain, BS3 must be met for BP7_Strong(RNA) eligibility, which is not satisfied. BP7_Supporting is restricted to silent/intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant inside RING domain
- BS3 not met
- BP7 not applicable for this variant type.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.558. BayesDel score = 0.0211131.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 11573085 ↗Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.Brzovic et al. solved the solution structure of the BRCA1-BARD1 heterodimeric RING-RING complex. The paper provides structural characterization of the RING domain interface but does not specifically report or characterize the NM_007294.4:c.19C>T (p.Arg7Cys) variant.Does not name this variant
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PMID 16267036 ↗Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.Judkins T et al. · 2005Judkins et al. describe an approach to characterize variants found in trans with known deleterious BRCA1 mutations using embryonic lethal phenotype. The paper discusses methodological principles for variant classification. NM_007294.4:c.19C>T was not specifically identified.Does not name this variant
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PMID 16403807 ↗Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility.Morris JR et al. · 2006Morris et al. analyzed BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility, focusing on the BRCA1-BARD1 RING heterodimer. The paper discusses cancer-associated missense mutations in the RING domain at a general level. NM_007294.4:c.19C>T was not specifically identified in this paper.Does not name this variant
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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.Joint consensus recommendation of the ACMG and AMP providing standards and guidelines for the interpretation of sequence variants. This is a methodological framework paper that does not discuss individual variants. NM_007294.4:c.19C>T was not identified.Does not name this variant
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PMID 25823446 ↗Massively Parallel Functional Analysis of BRCA1 RING Domain Variants.Starita LM et al. · 2015Starita et al. performed massively parallel functional analysis of nearly 2000 missense substitutions in the BRCA1 RING domain, measuring E3 ubiquitin ligase activity and BARD1 binding. c.19C>T (R7C) was among the variants assayed. The ENIGMA Table9 curates this as part of the calibrated functional dataset; results were discordant with Bouwman 2020.Names this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi et al. developed a standardized DNA variant scoring system (Sherloc) for pathogenicity assessments in Mendelian disorders. The paper describes a rules-based classification framework. NM_007294.4:c.19C>T was not specifically discussed.Does not name this variant
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PMID 32546644 ↗Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.Bouwman et al. performed functional categorization of BRCA1 variants of uncertain clinical significance using homologous recombination repair (HRR) complementation assays. c.19C>T (R7C) was tested and classified as Deleterious. This result was discordant with Findlay 2018 (PMID:30209399), which classified the variant as functionally normal.Names this variant
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PMID 35659930 ↗Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.Clark KA et al. · 2022Clark et al. performed comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions using multiplexed functional data. The study covers the RING domain (aa 2-101) including position 7 (Arg7Cys). ENIGMA incorporates this study's data into the calibrated functional reference set.Names this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp et al. presented Sherloc, a comprehensive refinement of the ACMG-AMP variant classification criteria. The paper is a methodological framework that does not discuss specific BRCA1 variants. NM_007294.4:c.19C>T was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
35 / 1,613,308 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.170
Open source ↗
ClinVar
11 Likely benign · 3 Uncertain significance · 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/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/37440/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41276095-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43124078-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43124078-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.19C%…
- OncoKB ↗www.oncokb.org/gene/BRCA1/R7C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=167902108
- 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= 2.16946e-05; MAF= 0.00217%, 35/1613308 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 1.884e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.38992e-05; MAF= 0.00239%, 6/251054 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2925e-05; MAF= 0.00529%, 6/113368 alleles, homozygotes = 0); grpmax FAF= 2.299e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 37440)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.558. BayesDel score = 0.0211131.
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; COSV100524047, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.