BRCA1c.5057A>GLikely pathogenic

Print report

Variant interpretation report

BRCA1 c.5057A>G, p.(His1686Arg)

NM_007294.4:c.5057A>G NP_009225.1:p.(His1686Arg) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BRCA1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen BRCA1 VCEP v1.2.0
Other laboratories (ClinVar): 5 Likely pathogenic · 3 Pathogenic · 1 pathogenic
Pipeline record: 7 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): Per ENIGMA Specifications Table 9, NM_007294.4:c.5057A>G (p.His1686Arg) is assigned PS3_Strong based on three calibrated functional studies that demonstrate protein function similar to pathogenic control variants: Findlay 2018 (PMID:30209399) saturation genome editing — classified as Loss-of-Function; Petitalot 2019 (PMID:30257991) — classified as 3P (pathogenic); and Bouwman 2020 (PMID:32546644) — classified as Deleterious. The variant shows complete functional impact (LOF, score -0.447) in the ST4 functional assay dataset and is annotated as LossOfFunction in ST13 with three supporting calibrated studies. SpliceAI max delta = 0.15 indicates no predicted splicing effect, confirming the functional defect is mediated at the protein level.
PM2 (supporting): NM_007294.4:c.5057A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls. In gnomAD v4.1, the variant is present at ultra-rare frequency (2/1,612,174 alleles; grpmax FAF=2.8e-07; highest in European non-Finnish at 2/1,178,240). The variant is also absent from gnomAD-Canada v1.0.
PP3 (supporting): NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.378, which exceeds the ENIGMA PP3 threshold of >=0.28 for predicted impact via protein change. REVEL score is 0.905, consistent with a deleterious prediction. SpliceAI max delta score is 0.15 (<0.2), indicating no significant predicted splicing impact.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PS3Strong

PS3 · strong

Per ENIGMA Specifications Table 9, NM_007294.4:c.5057A>G (p.His1686Arg) is assigned PS3_Strong based on three calibrated functional studies that demonstrate protein function similar to pathogenic control variants: Findlay 2018 (PMID:30209399) saturation genome editing — classified as Loss-of-Function; Petitalot 2019 (PMID:30257991) — classified as 3P (pathogenic); and Bouwman 2020 (PMID:32546644) — classified as Deleterious. The variant shows complete functional impact (LOF, score -0.447) in the ST4 functional assay dataset and is annotated as LossOfFunction in ST13 with three supporting calibrated studies. SpliceAI max delta = 0.15 indicates no predicted splicing effect, confirming the functional defect is mediated at the protein level.

PM2Supporting

PM2 · supporting

NM_007294.4:c.5057A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls. In gnomAD v4.1, the variant is present at ultra-rare frequency (2/1,612,174 alleles; grpmax FAF=2.8e-07; highest in European non-Finnish at 2/1,178,240). The variant is also absent from gnomAD-Canada v1.0.

PP3Supporting

PP3 · supporting

NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.378, which exceeds the ENIGMA PP3 threshold of >=0.28 for predicted impact via protein change. REVEL score is 0.905, consistent with a deleterious prediction. SpliceAI max delta score is 0.15 (<0.2), indicating no significant predicted splicing impact.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3 combination rules applied to adjudicated criteria: 1 Strong (PS3) + 2 Supporting (PM2, PP3) satisfies the Likely Pathogenic combination rule (1 Strong + ≥2 Supporting). No benign criteria are met, so no conflicting-evidence point-system reduction is required.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

2 / 1,612,174 alleles

gnomAD v4.1: 2 / 1,612,174 alleles. Recorded AF 1.24056e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.150 maximum delta

Recorded SpliceAI maximum delta score: 0.150. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

9 reported laboratory submissions

5 Likely pathogenic · 3 Pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → 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

COSMIC ↗Cancer Hotspots ↗

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: 3 met · 14 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant in BRCA1 exon 16, located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain critical for BRCA1 tumor suppressor activity.

The variant meets PS3_Strong per ENIGMA Specifications Table 9, based on three calibrated functional studies (Findlay 2018 PMID:30209399; Petitalot 2019 PMID:30257991; Bouwman 2020 PMID:32546644) that demonstrate protein function similar to pathogenic control variants, with complete functional impact (Loss-of-Function) confirmed in the ST4 functional assay dataset.

The variant meets PP3_Supporting: it is a missense substitution within the BRCT clinically important functional domain with a BayesDel no-AF score of 0.378 (>=0.28 threshold), predicting deleterious impact via protein change. REVEL score is 0.905. SpliceAI max delta is 0.15, indicating no significant splicing impact.

The variant meets PM2_Supporting: it is absent from gnomAD v2.1 (non-cancer, exome only) and present at ultra-rare frequency in gnomAD v4.1 (2/1,612,174 alleles; grpmax FAF=2.8e-07). It is absent from gnomAD-Canada v1.0.

PP4 could not be applied: the clinical-history likelihood ratio is LR=1.42 (1 proband, Li et al. 2020 PMID:31853058), which falls in the ENIGMA neutral zone (0.48-2.08) and provides insufficient evidence in either direction.

The variant does not meet PVS1 (missense, not a null variant), PS1 (no different nucleotide to same amino acid comparator), PS4 (no case-control study), PP1 (no co-segregation data), BA1/BS1 (frequency too low), BS2 (no healthy adult data), BS3 (functional evidence shows damaging effect), BS4 (no lack-of-segregation data), BP1 (inside functional domain), BP4 (BayesDel >0.15, SpliceAI >0.1), BP5 (LR neutral zone), or BP7 (damaging functional effect).

Met · 3

PS3 StrongPer ENIGMA Specifications Table 9, NM_007294.4:c.5057A>G (p.His1686Arg) is assigned PS3_Strong based on three calibrated functional studies that demonstrate protein function similar to pathogenic control variants: Findlay 2018 (PMID:30209399) saturation genome editing — classified as Loss-of-Function; Petitalot 2019 (PMID:30257991) — classified as 3P (pathogenic); and Bouwman 2020 (PMID:32546644) — classified as Deleterious. The variant shows complete functional impact (LOF, score -0.447) in the ST4 functional assay dataset and is annotated as LossOfFunction in ST13 with three supporting calibrated studies. SpliceAI max delta = 0.15 indicates no predicted splicing effect, confirming the functional defect is mediated at the protein level. Details ▾Hide ▴

Evidence considered

ENIGMA Table 9 assigns PS3_Strong with three calibrated studies
Findlay 2018 (PMID:30209399): saturation genome editing — Loss-of-Function
Petitalot 2019 (PMID:30257991): functional assay — 3P (pathogenic classification)
Bouwman 2020 (PMID:32546644): functional assay — Deleterious
ST4 functional assay: Functional impact - complete
LOF
score -0.447
ST13 bioinformatic: LossOfFunction
BayesDel 0.378
BRCT Repeats domain
3 studies

Sources

vcep_specifications_table9_v1_2_2024_11_18PMID:30209399 ↗vcep_supplementarytables_v1_2_2024_11_18

PM2 SupportingNM_007294.4:c.5057A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), meeting the ENIGMA PM2_Supporting criterion for absence from outbred population controls. In gnomAD v4.1, the variant is present at ultra-rare frequency (2/1,612,174 alleles; grpmax FAF=2.8e-07; highest in European non-Finnish at 2/1,178,240). The variant is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (non-cancer
exome only subset)
gnomAD v4.1: 2/1
612
174 alleles
grpmax FAF=2.8e-07 (ultra-rare)
Absent from gnomAD-Canada v1.0

Still missing

gnomAD v3.1 data not available for cross-reference

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP3 SupportingNM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.378, which exceeds the ENIGMA PP3 threshold of >=0.28 for predicted impact via protein change. REVEL score is 0.905, consistent with a deleterious prediction. SpliceAI max delta score is 0.15 (<0.2), indicating no significant predicted splicing impact. Details ▾Hide ▴

Evidence considered

Missense variant inside BRCT domain (aa 1686
within 1650-1857 clinically important functional domain)
BayesDel no-AF score = 0.378 >= 0.28 threshold
REVEL score = 0.905 (deleterious prediction)
SpliceAI max delta = 0.15 (no significant splicing impact)
ST13 confirms BRCT Repeats domain
LossOfFunction classification

Sources

bayesdelrevelspliceai ↗cspec ↗vcep_supplementarytables_v1_2_2024_11_18

Not met · 14 · evaluated, threshold not reached

PVS1 NM_007294.4:c.5057A>G is a missense variant (p.His1686Arg) in BRCA1 exon 16. PVS1 applies only to null variants (nonsense, frameshift, canonical +/-1,2 splice site, initiation codon, or exon deletion). This variant does not fall into any of those categories and the generic PVS1 framework is not applicable per ENIGMA VCEP v1.2.0. Details ▾Hide ▴

Evidence considered

Missense substitution
not a null variant
pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false
BRCA1 LOF mechanism is supported per VCEP but this variant class does not trigger PVS1

Sources

pvs1_variant_assessmentpvs1_gene_context

PS1 No different nucleotide change at codon 1686 producing the same amino acid substitution (His1686Arg) has been classified as pathogenic. A single nucleotide change from CAC (His) to CGC (Arg) at c.5057A>G is the only single-nucleotide path to His1686Arg in the standard genetic code. No comparator variant meeting PS1 criteria was identified. Details ▾Hide ▴

Evidence considered

No known pathogenic variant with the same amino acid change (His1686Arg) from a different nucleotide substitution at this codon

PS4 No case-control study demonstrating significantly increased prevalence of NM_007294.4:c.5057A>G in affected individuals versus controls (p-value <= 0.05 and OR >= 4, lower CI excluding 2.0) was identified. The variant is reported in ClinVar as Likely pathogenic/Pathogenic by multiple clinical laboratories, but this reflects aggregate clinical observations rather than a formal case-control study meeting ENIGMA PS4 evidentiary thresholds. Details ▾Hide ▴

Evidence considered

ClinVar: Likely pathogenic (5 labs)
Pathogenic (3 labs)
pathogenic (1 lab)
No formal case-control study with p<=0.05 and OR>=4 identified

Still missing

No case-control study data available for this specific variant

Sources

clinvar ↗

PP1 No co-segregation data are available for NM_007294.4:c.5057A>G. A quantitative co-segregation analysis (LR >= 2.08 for PP1_Supporting) has not been performed for this variant. Details ▾Hide ▴

Evidence considered

No co-segregation studies identified

Still missing

No co-segregation data available

PP4 The clinical-history likelihood ratio for NM_007294.4:c.5057A>G is LR = 1.42 (based on 1 proband, from Li et al. 2020 PMID:31853058). This falls within the ENIGMA neutral zone (>0.48 and <2.08), where neither PP4 nor BP5 can be applied. The evidence is insufficient to support pathogenicity or benignity from personal/family history data. Details ▾Hide ▴

Evidence considered

Clinical history LR = 1.42 (1 proband)
LR falls in neutral zone (0.48 < LR < 2.08)

Still missing

Only 1 proband available
larger cohort could strengthen or refute

Sources

PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr

BA1 The grpmax filter allele frequency (FAF) for NM_007294.4:c.5057A>G in gnomAD v4.1 is 2.8e-07 (0.000028%), which is far below the ENIGMA BA1 threshold of FAF > 0.1% (0.001). The variant is absent from gnomAD v2.1. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: grpmax FAF = 2.8e-07 (<< 0.001 threshold)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The grpmax FAF of 2.8e-07 is below both the ENIGMA BS1_Strong threshold (FAF > 0.0001, i.e., >0.01%) and the BS1_Supporting threshold (FAF > 0.00002 and <= 0.0001, i.e., >0.002% and <=0.01%). The variant does not meet any BS1 strength level. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 2.8e-07 (<< 0.00002 BS1_Supporting threshold)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No data are available for observation of NM_007294.4:c.5057A>G in healthy adults without features of Fanconi Anemia. BS2 requires specific proband-level data per ENIGMA Specifications Table 8 point system, which has not been assembled for this variant. Details ▾Hide ▴

Evidence considered

No proband-level data for BS2 point assignment available

Still missing

No healthy adult observation data available

BS3 ENIGMA Specifications Table 9 assigns PS3_Strong, not BS3, for NM_007294.4:c.5057A>G. Three calibrated functional studies demonstrate a damaging effect on protein function (Loss-of-Function). No well-established functional studies show no damaging effect; the evidence direction is uniformly pathogenic. Details ▾Hide ▴

Evidence considered

ENIGMA Table 9: PS3_Strong assigned
no BS3
ST4 functional assay: Functional impact - complete
LOF
All functional evidence points toward damaging effect

Sources

vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18

BS4 No quantitative co-segregation analysis demonstrating lack of segregation with disease (LR <= 0.48 for BS4_Supporting) has been performed for NM_007294.4:c.5057A>G. Details ▾Hide ▴

Evidence considered

No lack-of-segregation studies identified

Still missing

No co-segregation data available

BP1 NM_007294.4:c.5057A>G (p.His1686Arg) is a missense variant located within the BRCT repeat domain (aa 1650-1857), which is a clinically important functional domain per ENIGMA specifications. BP1_Strong requires the variant to be located OUTSIDE a clinically important functional domain with no predicted splicing (SpliceAI <= 0.1). Since this variant is inside the BRCT domain, BP1 cannot be applied. Details ▾Hide ▴

Evidence considered

Missense variant INSIDE BRCT domain (aa 1686
within 1650-1857)
BP1 requires location outside clinically important functional domain

Sources

cspec ↗

BP4 BP4_Supporting requires: (a) missense variant inside a clinically important functional domain, AND (b) BayesDel no-AF score <= 0.15, AND (c) SpliceAI <= 0.1. While this variant is inside the BRCT domain, the BayesDel score is 0.378 (>0.15 threshold) and SpliceAI max delta is 0.15 (>0.1 threshold). Neither computational criterion for BP4 is met. Details ▾Hide ▴

Evidence considered

BayesDel = 0.378 (> 0.15 BP4 threshold)
SpliceAI max delta = 0.15 (> 0.1 BP4 threshold)
Variant is inside BRCT domain (meets location criterion)

Sources

bayesdelspliceai ↗cspec ↗

BP5 The clinical-history likelihood ratio for NM_007294.4:c.5057A>G is LR = 1.42 (based on 1 proband). This falls within the ENIGMA neutral zone (>0.48 and <2.08). BP5 cannot be applied; the evidence neither supports nor refutes pathogenicity from personal/family history data. Details ▾Hide ▴

Evidence considered

Clinical history LR = 1.42 (1 proband)
LR falls in neutral zone (0.48 < LR < 2.08)

Still missing

Only 1 proband available

Sources

PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr

BP7 NM_007294.4:c.5057A>G is a missense variant. BP7_Strong (RNA) would require well-established functional studies showing no damaging effect on mRNA transcript profile, but all functional evidence (ENIGMA Table 9 PS3_Strong, ST4 LOF) demonstrates a damaging effect. BP7_Supporting requires a silent variant inside a clinically important functional domain with BP4 met — this variant is missense, not silent, so BP7_Supporting does not apply. Details ▾Hide ▴

Evidence considered

Missense variant
not silent — BP7_Supporting not applicable
Functional studies show damaging effect — BP7_Strong (RNA) not applicable

Sources

cspec ↗vcep_specifications_table9_v1_2_2024_11_18

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS2 VCEPPS2 (de novo) is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

PM1 VCEPPM1 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

PM5 N/APM5 in the ENIGMA BRCA1/BRCA2 specification is repurposed for protein termination codon (PTC) variants (PM5_PTC) — applied to PTC variants in exons where a different proven pathogenic PTC variant has been observed. NM_007294.4:c.5057A>G is a missense variant (p.His1686Arg), not a PTC variant. Classic same-residue missense PM5 is not used in the ENIGMA framework for BRCA1. Details ▾Hide ▴

Evidence considered

Missense variant
not a PTC variant
ENIGMA PM5 is repurposed for PTC logic only

Sources

pm5_candidatescspec ↗

PM6 VCEPPM6 (de novo) is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPPP2 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

PP5 VCEPPP5 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPBP2 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

BP6 VCEPBP6 is designated as Not Applicable in the ENIGMA BRCA1 and BRCA2 Expert Panel Specifications version 1.2.0. Details ▾Hide ▴

Sources

cspec ↗

PS5 N/APS5 is not included in the ENIGMA BRCA1/BRCA2 VCEP v1.2.0 criteria. The closest criterion, PP5 (reputable source recently reports variant as pathogenic), is designated as Not Applicable in the ENIGMA specification. Details ▾Hide ▴

Sources

cspec ↗

Identifiers

Gene: BRCA1
Transcript: NM_007294.4
Coding (HGVS c.): NM_007294.4:c.5057A>G
Protein (HGVS p.): NP_009225.1:p.(His1686Arg)
GRCh38: chr17:43067625 T>C
GRCh37: chr17:41219642 T>C
ClinVar: 868612, 868586, 867514, 867446, 867391, 867297, 867287, 580844, 183179, 141467

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

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in BRCA1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 2 / 1,612,174 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,612,174 alleles · 0 hom · FAF 2.8e-07

European (non-Finnish)2 / 1,178,240

1.7e-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.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.24056e-06; MAF= 0.00012%, 2/1612174 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69745e-06; MAF= 0.00017%, 2/1178240 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -18 bp

0.010

SpliceAI acceptor gainat +70 bp

0.090

SpliceAI donor lossat -1 bp

0.000

SpliceAI donor gainat -17 bp

0.150

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.080

Other predictors

REVEL: 0.905
BayesDel: 0.378

How the predictions were used

Evidence considered

Missense variant inside BRCT domain (aa 1686
within 1650-1857 clinically important functional domain)
BayesDel no-AF score = 0.378 >= 0.28 threshold
REVEL score = 0.905 (deleterious prediction)
SpliceAI max delta = 0.15 (no significant splicing impact)
ST13 confirms BRCT Repeats domain
LossOfFunction classification

Sources

bayesdelrevelspliceai ↗cspec ↗vcep_supplementarytables_v1_2_2024_11_18

Evidence considered

BayesDel = 0.378 (> 0.15 BP4 threshold)
SpliceAI max delta = 0.15 (> 0.1 BP4 threshold)
Variant is inside BRCT domain (meets location criterion)

Sources

bayesdelspliceai ↗cspec ↗

Evidence considered

Missense variant
not silent — BP7_Supporting not applicable
Functional studies show damaging effect — BP7_Strong (RNA) not applicable

Sources

cspec ↗vcep_specifications_table9_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.905. BayesDel score = 0.378152.

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

Accurate classification of BRCA1 variants with saturation genome editing.

Findlay GM et al. · 2018 Oct

Findlay et al. 2018 performed saturation genome editing of BRCA1 RING and BRCT domain exons, functionally classifying 3,893 SNVs. The variant NM_007294.4:c.5057A>G (p.His1686Arg) was among the variants assayed but is listed only in supplementary tables, not in the main text. The ENIGMA VCEP curated the supplementary data and determined the variant exhibits complete Loss-of-Function.
→ PS3 Does not name this variant
PMID 30209399 ↗
Source detail

Location Supplementary Table 1 (online at sge.gs.washington.edu/BRCA1); main text describes methodology for all BRCT domain variants in exon 16

Context Saturation genome editing in HAP1 haploid cells, survival-based assay measuring HDR pathway function

Other recorded publications

A high-throughput functional complementation assay for classification of BRCA1 missense variants.

Bouwman P et al. · 2013

Bouwman et al. 2013 developed a high-throughput functional complementation assay for BRCA1 missense variant classification using Brca1-mutant mouse embryonic stem cell viability. While this paper describes the assay platform later used for calibrated variant classification (e.g., Bouwman 2020 PMID:32546644), the specific variant NM_007294.4:c.5057A>G was not mentioned in this 2013 publication. The variant was subsequently assessed in the 2020 calibrated study.
Does not name this variant
PMID 23867111 ↗
Mutations in the BRCT domain confer temperature sensitivity to BRCA1 in transcription activation.

Carvalho MA et al. · 2002

Carvalho et al. 2002 used random mutagenesis of the BRCA1 C-terminal BRCT domain to study temperature-sensitive effects on transcriptional activation. This study predates the identification of NM_007294.4:c.5057A>G and does not mention this specific variant.
Does not name this variant
PMID 12496477 ↗
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.

Richards et al. 2015 provides the ACMG/AMP standards and guidelines for sequence variant interpretation. This is a methodology and framework paper that does not discuss individual BRCA1 variants. NM_007294.4:c.5057A>G was not identified in this publication.
Does not name this variant
PMID 25741868 ↗
Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review.

Minucci A et al. · 2015

Minucci et al. 2015 evaluated a massive parallel sequencing pipeline for BRCA1/2 testing in 212 Italian ovarian cancer patients. NM_007294.4:c.5057A>G was not identified in the abstract or available publication text.
Does not name this variant
PMID 26306726 ↗
Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.

Wen WX et al. · 2018

Wen et al. 2018 performed full BRCA1/2 exon screening in 2,575 unselected Asian breast cancer patients and 2,809 controls from Malaysia. The study reports aggregate mutation frequencies but does not list individual missense VUS by HGVS. NM_007294.4:c.5057A>G was not identified in the published text.
Does not name this variant
PMID 28993434 ↗
Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction.

Huang C et al. · 2021

Huang et al. 2021 describes a base editing screen with editing efficiency correction for identifying pathogenic variants in cancer genes. The paper discusses methodology applied to BRCA1 but NM_007294.4:c.5057A>G was not identified in the publication text or supplementary materials available.
Does not name this variant
PMID 33691754 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,612,174 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.150 Open source ↗

ClinVar 5 Likely pathogenic · 3 Pathogenic · 1 pathogenic 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

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 Likely pathogenic (5 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 183179)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.905. BayesDel score = 0.378152.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.