About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.3170G>A, p.(Ser1057Asn)
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
BP1Strong
BP1 · strong
ENIGMA BP1_Strong applies to missense variants located outside the clinically important functional domains of BRCA1 when no splicing is predicted. p.Ser1057Asn is at amino acid position 1057, which lies in the exon 11 spacer region (aa 224-1366), well outside the RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI max delta score is 0.0, confirming no predicted splicing impact. This region has been characterized as a coldspot with zero pathogenic/likely pathogenic missense variants among 1,117 exon 11 missense variants in ClinVar (Dines et al. 2020, PMID:31911673).
Recorded classification: Uncertain significance
ENIGMA BRCA1 v1.2 Table 3 categorical rules applied. Only BP1_Strong is met (missense variant outside clinically important functional domains, no splicing predicted). ENIGMA Likely Benign rule for a single Strong Benign criterion requires multiple independent evidence types; BP1 alone constitutes a single evidence type (coldspot/domain location). No other benign criteria are met. The variant does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination rule, and therefore defaults to Uncertain Significance.
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
3 / 1,613,924 alleles
gnomAD v4.1: 3 / 1,613,924 alleles. Recorded AF 1.85882e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98686e-06; MAF= 0.00040%, 1/250824 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83455e-06; MAF= 0.00088%, 1/113192 alleles, homozygotes = 0).
gnomAD-Canada
Not available in 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
6 reported laboratory submissions
5 Uncertain significance · 1 Uncertain Significance. 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; COSV58797942, 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, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 9 not met · 6 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
c.3170G>A (p.Ser1057Asn) is a missense variant in BRCA1 exon 10 (legacy exon 11) located at amino acid position 1057, outside the established clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857).
SpliceAI predicts no splicing impact (max delta score 0.00), and BayesDel no-AF score is -0.0291, consistent with a benign computational prediction.
BP1_Strong is met: the variant is a missense substitution outside clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). This is the only applicable ACMG/AMP criterion supported by current evidence.
BRCA1 exon 11 (aa 224-1366), where p.Ser1057Asn resides, has been characterized as a coldspot with zero pathogenic or likely pathogenic missense variants among 1,117 exon 11 missense variants reported to ClinVar.
The variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/250,824 alleles, AF=0.0004%; gnomAD v4.1: 3/1,613,924 alleles, grpmax FAF=6.8e-7), below thresholds for both benign (BS1) and pathogenic (PM2) population criteria.
No functional data, case-control studies, segregation analysis, clinical history likelihood ratios, or variant-specific publications were identified for this variant. It is reported in ClinVar as Uncertain Significance (5 clinical laboratories, single submitter criteria only, no expert panel review).
Under the ENIGMA BRCA1 v1.2 point-based classification system, the evidence totals -4 points (BP1_Strong alone), placing the variant in the Likely Benign range (-6 to -2). However, ENIGMA Table 3 requires multiple evidence types to support Likely Benign when based on a single Strong Benign criterion. With only BP1_Strong met and no additional benign criteria satisfied from independent evidence types, the classification defaults to Uncertain Significance per the ENIGMA adapted ACMG/AMP framework.
No criteria match.
Met · 1
BP1 StrongENIGMA BP1_Strong applies to missense variants located outside the clinically important functional domains of BRCA1 when no splicing is predicted. p.Ser1057Asn is at amino acid position 1057, which lies in the exon 11 spacer region (aa 224-1366), well outside the RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI max delta score is 0.0, confirming no predicted splicing impact. This region has been characterized as a coldspot with zero pathogenic/likely pathogenic missense variants among 1,117 exon 11 missense variants in ClinVar (Dines et al. 2020, PMID:31911673). Details ▾Hide ▴
Evidence considered
- Missense variant at aa 1057
- outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) functional domains.
- SpliceAI max delta = 0.0 (≤0.1
- no splicing predicted).
- BRCA1 exon 11 region (aa 224-1366) has 0 P/LP missense variants among 1
- 117 submitted to ClinVar per Dines 2020.
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No previously classified pathogenic or likely pathogenic missense variant was identified at the same amino acid residue (Ser1057) in ClinVar or ENIGMA reference datasets. ENIGMA PS1 requires a same-residue pathogenic comparator with the same predicted impact on protein or splicing, which is not available for this variant. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variant at residue S1057 identified in ClinVar or ENIGMA reference set ST7.
Sources
clinvar ↗vcep_supplementarytables_v1_2_2024_11_18
PS3 c.3170G>A (p.Ser1057Asn) is not listed in ENIGMA Table 9 curated functional assay results and is not present in Supplementary Table 4 functional assay data. No variant-specific functional studies demonstrating a damaging effect were identified in the reviewed literature. The variant falls within BRCA1 exon 11 spacer region (aa 224-1366), which is outside the established clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). Details ▾Hide ▴
Evidence considered
- Not present in ENIGMA Table 9 (PS3/BS3 assignments).
- Not present in ST4 functional assay results.
- OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.
Still missing
- No functional assay data available for this variant.
Sources
PM2 ENIGMA PM2_Supporting requires the variant to be absent from gnomAD v2.1 (non-cancer, exome) and v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 (1/250824 alleles, AF=3.99e-6) and gnomAD v4.1 (3/1613924 alleles, AF=1.86e-6). Per ENIGMA guidance, observation even once in an outbred population is not informative for PM2 and the criterion does not apply. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/250824 alleles (AF=3.99e-6
- NFE).
- gnomAD v4.1: 3/1613924 alleles (AF=1.86e-6
- grpmax FAF=6.8e-7).
- Variant is present
- therefore absent-from-controls criterion not satisfied.
Sources
PP3 ENIGMA PP3 for missense variants requires the variant to be located inside a clinically important functional domain with BayesDel ≥0.28, or SpliceAI ≥0.2 for splicing prediction. p.Ser1057Asn is at amino acid position 1057, which lies outside the established BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel score is -0.0291 (<0.28) and SpliceAI max delta is 0.0 (<0.2). Neither protein-level nor splicing-level PP3 conditions are satisfied. Details ▾Hide ▴
Evidence considered
- Position aa 1057 is outside known functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857).
- BayesDel no-AF score = -0.0291 (<0.28 threshold).
- SpliceAI max delta = 0.0 (<0.2 threshold).
- REVEL = 0.543 (intermediate
- not used independently in ENIGMA PP3).
Sources
BA1 BA1 requires filter allele frequency (FAF) > 0.1% (0.001) in gnomAD non-cancer, non-founder populations. The variant's maximum FAF is 6.8e-7 (gnomAD v4.1 grpmax), far below the BA1 threshold of 0.001. This variant is extremely rare in population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 6.8e-7 (<< 0.001 BA1 threshold).
- gnomAD v2.1 max AF = 8.83e-6 (NFE population).
Sources
BS1 ENIGMA BS1_Strong requires FAF > 0.01% (0.0001) and BS1_Supporting requires FAF > 0.002% (0.00002). The variant's highest FAF is 8.83e-6 in gnomAD v2.1 NFE (0.00088%), which is below even the BS1_Supporting threshold of 0.00002 (0.002%). The variant is too rare to satisfy BS1 at any strength. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 NFE AF = 8.83e-6 (0.00088% << 0.002% BS1_Supporting threshold).
- gnomAD v4.1 grpmax FAF = 6.8e-7 (<< BS1_Supporting).
Sources
BS3 c.3170G>A (p.Ser1057Asn) is not listed in ENIGMA Table 9 with a BS3 assignment and is not present in Supplementary Table 4 functional assay results with an outcome of no functional impact. No variant-specific functional studies demonstrating a neutral or non-damaging effect were identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- Not present in ENIGMA Table 9 BS3 assignments.
- Not present in ST4 functional assay results with no-impact outcome.
Still missing
- No functional data demonstrating neutral effect.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BP4 ENIGMA BP4 for missense variants requires the variant to be located inside a clinically important functional domain AND have no predicted impact (BayesDel ≤0.15 AND SpliceAI ≤0.1). While the BayesDel score (-0.0291) and SpliceAI (0.0) satisfy the prediction thresholds, the variant is located at aa 1057, outside the defined BRCA1 functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The domain-location condition for BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel = -0.0291 (≤0.15
- benign prediction).
- SpliceAI = 0.0 (≤0.1
- no splicing).
- Position aa 1057 is outside functional domains
- BP4 domain condition not satisfied.
Sources
BP7 ENIGMA BP7_Strong (RNA) for missense variants outside functional domains requires well-established mRNA assay data demonstrating no splicing impact. No mRNA transcript analysis data are available for c.3170G>A. BP7_Supporting applies only to silent or intronic variants, not missense. Although SpliceAI predicts no splicing impact (delta=0.0), ENIGMA requires direct experimental mRNA evidence for BP7 application to missense variants. Details ▾Hide ▴
Evidence considered
- No mRNA transcript or minigene assay data available.
- SpliceAI predicts no splicing impact (delta=0.0) but direct experimental evidence is required for BP7.
Still missing
- No mRNA splicing assay data for this variant.
Sources
Not assessed · 6 · no assessment recorded
PS4 No case-control data are available for this variant. ENIGMA PS4 requires case-control studies with p≤0.05 and OR≥4 (lower CI excludes 2.0). No such study was identified in the case materials or literature. Details ▾Hide ▴
Evidence considered
- No case-control study identified.
Still missing
- No case-control data available.
PP1 No co-segregation data are available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR≥2.08. No segregation data were identified in the case materials or reviewed literature. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No segregation analysis data.
PP4 ENIGMA PP4 requires calibrated clinical history likelihood ratio data (LR≥2.08). The variant c.3170G>A is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical history LR table, and is not listed in the Parsons et al. 2019 (PMID:31131967) multifactorial likelihood dataset. No clinical history LR toward pathogenicity is available. Details ▾Hide ▴
Evidence considered
- Not present in Li 2020 BRCA1 clinical history LR table.
- Not present in Parsons 2019 HUMU multifactorial dataset.
Still missing
- No clinical history likelihood ratio data available.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001
BS2 ENIGMA BS2 requires co-observation data in the absence of Fanconi Anemia phenotype features, with point-based scoring per proband. No co-observation data for this variant were identified in the case materials or literature. Details ▾Hide ▴
Evidence considered
- No co-observation data available.
Still missing
- No co-observation or co-occurrence data.
BS4 ENIGMA BS4 requires lack of segregation in affected family members, measured by quantitative co-segregation analysis (LR≤0.48). No segregation data for this variant were identified. Details ▾Hide ▴
Evidence considered
- No lack-of-segregation data available.
Still missing
- No segregation analysis data.
BP5 ENIGMA BP5 requires calibrated clinical history likelihood ratio data toward benignity (LR≤0.48). The variant c.3170G>A is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical history LR table and is not listed in the Parsons et al. 2019 (PMID:31131967) multifactorial dataset. No LR toward benignity is available. Details ▾Hide ▴
Evidence considered
- Not present in Li 2020 clinical history LR table.
- Not present in Parsons 2019 multifactorial dataset.
Still missing
- No clinical history LR toward benignity.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_007294.4:c.3170G>A is a missense substitution (p.Ser1057Asn), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). ENIGMA BRCA1 PVS1 rules apply only to null variants per Specifications Table 4. Details ▾Hide ▴
Evidence considered
- Missense variant
- does not fall into any PVS1 null-variant bucket.
Sources
pvs1_generic_framework ↗vcep_specifications_table4_v1_2_2024_11_18
PS2 VCEPENIGMA BRCA1 VCEP marks PS2 (de novo) as Not Applicable. BRCA1/2-related cancers occur relatively commonly and de novo occurrence data cannot be calibrated for these genes. Details ▾Hide ▴
PM1 VCEPENIGMA BRCA1 VCEP marks PM1 as Not Applicable. The criterion is considered as a component of the bioinformatic analysis under PP3/BP4. Domain-level assessment is integrated into those codes rather than applied as a standalone PM1. Details ▾Hide ▴
PM5 N/AENIGMA BRCA1 repurposes PM5 for protein termination codon (PTC) variants in exons where a proven pathogenic PTC variant has been observed (PM5_PTC). c.3170G>A is a missense variant, not a PTC variant. Classic same-residue missense PM5 is not applicable in the ENIGMA framework for BRCA1. Details ▾Hide ▴
Evidence considered
- Missense variant
- PM5_PTC logic applies only to truncating variants.
Sources
vcep_specifications_table4_v1_2_2024_11_18
PM6 VCEPENIGMA BRCA1 VCEP marks PM6 (assumed de novo) as Not Applicable. BRCA1/2-related cancers occur relatively commonly, and there is insufficient information to calibrate the predictive capacity of de novo occurrences for these genes. Details ▾Hide ▴
PP2 VCEPENIGMA BRCA1 VCEP marks PP2 as Not Applicable. Details ▾Hide ▴
PP5 VCEPENIGMA BRCA1 VCEP marks PP5 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. This criterion is not for use in this VCEP framework. Details ▾Hide ▴
BP2 VCEPENIGMA BRCA1 VCEP marks BP2 as Not Applicable. This criterion is applied only in the context of BS2, which is not assessed here. Details ▾Hide ▴
BP6 VCEPENIGMA BRCA1 VCEP marks BP6 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. This criterion is not for use in this VCEP framework. Details ▾Hide ▴
PS5 N/APS5 is not a standard ACMG/AMP evidence criterion and is not defined in the ENIGMA BRCA1 VCEP specifications version 1.2. No applicable rule exists for this code. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.3170G>A
- Protein (HGVS p.)
- NP_009225.1:p.(Ser1057Asn)
- GRCh38
- chr17:43092361 C>T
- GRCh37
- chr17:41244378 C>T
- ClinVar
- 939559, 630188, 156191, 96913
- COSMIC
- COSV58797942
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
3 / 1,613,924 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
1 / 250,824 alleles
AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,924 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,179,976 | 2.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 250,824 alleles · 0 hom
| European (non-Finnish)1 / 113,192 | 8.8e-06 |
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= 1.85882e-06; MAF= 0.00019%, 3/1613924 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54242e-06; MAF= 0.00025%, 3/1179976 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98686e-06; MAF= 0.00040%, 1/250824 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83455e-06; MAF= 0.00088%, 1/113192 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.543
- BayesDel
- -0.029
How the predictions were used
PP3 ENIGMA PP3 for missense variants requires the variant to be located inside a clinically important functional domain with BayesDel ≥0.28, or SpliceAI ≥0.2 for splicing prediction. p.Ser1057Asn is at amino acid position 1057, which lies outside the established BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel score is -0.0291 (<0.28) and SpliceAI max delta is 0.0 (<0.2). Neither protein-level nor splicing-level PP3 conditions are satisfied. Details ▾Hide ▴
Evidence considered
- Position aa 1057 is outside known functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857).
- BayesDel no-AF score = -0.0291 (<0.28 threshold).
- SpliceAI max delta = 0.0 (<0.2 threshold).
- REVEL = 0.543 (intermediate
- not used independently in ENIGMA PP3).
Sources
BP4 ENIGMA BP4 for missense variants requires the variant to be located inside a clinically important functional domain AND have no predicted impact (BayesDel ≤0.15 AND SpliceAI ≤0.1). While the BayesDel score (-0.0291) and SpliceAI (0.0) satisfy the prediction thresholds, the variant is located at aa 1057, outside the defined BRCA1 functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). The domain-location condition for BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel = -0.0291 (≤0.15
- benign prediction).
- SpliceAI = 0.0 (≤0.1
- no splicing).
- Position aa 1057 is outside functional domains
- BP4 domain condition not satisfied.
Sources
BP7 ENIGMA BP7_Strong (RNA) for missense variants outside functional domains requires well-established mRNA assay data demonstrating no splicing impact. No mRNA transcript analysis data are available for c.3170G>A. BP7_Supporting applies only to silent or intronic variants, not missense. Although SpliceAI predicts no splicing impact (delta=0.0), ENIGMA requires direct experimental mRNA evidence for BP7 application to missense variants. Details ▾Hide ▴
Evidence considered
- No mRNA transcript or minigene assay data available.
- SpliceAI predicts no splicing impact (delta=0.0) but direct experimental evidence is required for BP7.
Still missing
- No mRNA splicing assay data for this variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.543. BayesDel score = -0.0291003.
7 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
-
PMID 31911673 ↗Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".Dines JN et al. · 2020 MayIdentifies BRCA1 exon 11 (aa 224-1366) as a coldspot with zero pathogenic or likely pathogenic missense variants among 1,117 exon 11 missense variants submitted to ClinVar. Proposes using coldspot regions as benign evidence for variant classification. p.Ser1057Asn falls within this coldspot region.→ BP1 Does not name this variant
Source detail
Exon 11 in BRCA1... 0 (0%) P or LP [pathogenic or likely pathogenic] out of 1,117 total missense variants.
Location Results, Table 1; entire discussion of exon 11 coldspot (aa 224-1366)
Other recorded publications
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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.ACMG/AMP 2015 standards and guidelines for interpretation of sequence variants. Provides the foundational framework for variant classification but does not discuss BRCA1 c.3170G>A or any specific variant.Does not name this variant
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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 guidelines for breast screening with MRI as an adjunct to mammography. General screening guideline; does not discuss specific BRCA1 variants.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.NSGC practice guideline for risk assessment and genetic counseling for hereditary breast and ovarian cancer. Provides clinical practice recommendations for BRCA1/2 genetic testing but does not discuss specific variants.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 recommendation statement on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Population-level screening guideline; does not discuss specific BRCA1 variants.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 cancer. Brief lay-language summary; no variant-level content.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.ASCO expert statement on collection and use of cancer family history for oncology providers. Practice guidance document; does not discuss specific BRCA1 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,613,924 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
5 Uncertain significance · 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/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/156191/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41244378-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43092361-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43092361-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.3170…
- OncoKB ↗www.oncokb.org/gene/BRCA1/S1057N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=167928039
- 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= 1.85882e-06; MAF= 0.00019%, 3/1613924 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54242e-06; MAF= 0.00025%, 3/1179976 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98686e-06; MAF= 0.00040%, 1/250824 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83455e-06; MAF= 0.00088%, 1/113192 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 156191)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.543. BayesDel score = -0.0291003.
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; COSV58797942, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.