BRCA1c.5194-12G>ALikely pathogenic

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Variant interpretation report

BRCA1 c.5194-12G>A, p.?

NM_007294.4:c.5194-12G>A NP_009225.1:p.? 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) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA1 VCEP v1.2.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): This intronic variant is outside the canonical +/-1,2 splice site, so default generic PVS1 does not apply. However, BRCA1 loss of function is an established disease mechanism, and RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), consistent with a loss-of-function transcript. Under the ENIGMA BRCA1/2 RNA-splicing framework, this supports PVS1 at Strong strength.
PP4 (moderate): Clinical-history likelihood-ratio analysis for BRCA1 reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA PP4_Moderate threshold of 4.3 and below the PP4_Strong threshold of 18.7, supporting PP4 at Moderate strength.
PP5 (supporting): Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

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

PVS1Strong

PVS1 · strong

This intronic variant is outside the canonical +/-1,2 splice site, so default generic PVS1 does not apply. However, BRCA1 loss of function is an established disease mechanism, and RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), consistent with a loss-of-function transcript. Under the ENIGMA BRCA1/2 RNA-splicing framework, this supports PVS1 at Strong strength.

PP4Moderate

PP4 · moderate

Clinical-history likelihood-ratio analysis for BRCA1 reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA PP4_Moderate threshold of 4.3 and below the PP4_Strong threshold of 18.7, supporting PP4 at Moderate strength.

PP5Supporting

PP5 · supporting

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 adapted ACMG/AMP criteria-combination rules

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 / 1,612,068 alleles

gnomAD v4.1: 2 / 1,612,068 alleles. Recorded AF 1.24064e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Applied · PP5 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 6 not met · 6 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The BRCA1 c.5194-12G>A (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as pathogenic.

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07).

RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), which is consistent with a loss-of-function splice effect and supports PVS1 at Strong strength under the ENIGMA BRCA1/2 RNA framework.

SpliceAI predicts a strong splice impact for this variant with a maximum delta score of 0.96.

In the ENIGMA BRCA1 clinical-history model, this variant had a likelihood ratio of 12.3447 in 1 proband, which meets PP4 at Moderate strength.

Met · 3

PVS1 StrongThis intronic variant is outside the canonical +/-1,2 splice site, so default generic PVS1 does not apply. However, BRCA1 loss of function is an established disease mechanism, and RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), consistent with a loss-of-function transcript. Under the ENIGMA BRCA1/2 RNA-splicing framework, this supports PVS1 at Strong strength. Details ▾Hide ▴

Rule

ENIGMA PVS1 RNA framework for mRNA-only evidence supporting a damaging splice effect.

Evidence considered

BRCA1 loss of function is an established disease mechanism in the ENIGMA framework.
Splicing studies reported retention of 10 nt of intron 19.
The variant is outside the canonical +/-1
2 splice positions.

Still missing

The retrieved RNA studies did not provide quantitative per-allele transcript proportions.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:21394826 ↗PMID:21673748 ↗

PP4 ModerateClinical-history likelihood-ratio analysis for BRCA1 reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA PP4_Moderate threshold of 4.3 and below the PP4_Strong threshold of 18.7, supporting PP4 at Moderate strength. Details ▾Hide ▴

Rule

ENIGMA PP4 thresholds: Supporting >=2.08, Moderate >=4.3, Strong >=18.7, Very Strong >=350.

Evidence considered

Clinical-history LR 12.3447196932389
N_Probands 1

Sources

cspec ↗PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lrvcep_pmid_31853058_li_2020_geneticsinmedicine

PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴

Evidence considered

PP5 is marked not applicable in the BRCA1 specification.
ClinVar expert panel classification

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18clinvar ↗

Not met · 6 · evaluated, threshold not reached

PM2 This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07). ENIGMA PM2_Supporting requires absence from the specified population datasets, and this observation does not meet that requirement. Details ▾Hide ▴

Rule

ENIGMA PM2_Supporting requires absence from controls; a single outbred observation is not informative.

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: AF 1.24064e-06
2 alleles
grpmax FAF 2.8e-07

Still missing

No gnomAD v3.1 record was retrieved.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18

BA1 The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴

Rule

ENIGMA BA1 requires FAF >0.001 in a non-founder population.

Evidence considered

gnomAD v4.1 grpmax FAF 2.8e-07

Sources

cspec ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18

BS1 The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and well below the BS1 threshold of 0.0001. Details ▾Hide ▴

Rule

ENIGMA BS1 thresholds: Supporting >0.00002 to <=0.0001; Strong >0.0001.

Evidence considered

gnomAD v4.1 grpmax FAF 2.8e-07

Sources

cspec ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18

BP4 For intronic variants outside the native splice sites, ENIGMA BP4 requires no predicted splice impact with SpliceAI <=0.1. This variant has a SpliceAI maximum delta score of 0.96, which is above that threshold and argues against BP4. Details ▾Hide ▴

Rule

ENIGMA BP4 requires SpliceAI <=0.1 for eligible intronic variants.

Evidence considered

SpliceAI max delta score 0.96

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

BP5 Clinical-history likelihood-ratio analysis reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA neutral-zone upper boundary of 2.08 and well above the BP5 threshold of 0.48, so BP5 is not met. Details ▾Hide ▴

Rule

ENIGMA BP5 thresholds: Supporting <=0.48, Moderate <=0.23, Strong <=0.05, Very Strong <=0.00285.

Evidence considered

Clinical-history LR 12.3447196932389
N_Probands 1

Sources

cspec ↗PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lrvcep_pmid_31853058_li_2020_geneticsinmedicine

BP7 ENIGMA BP7 is used for variants with no predicted splice impact or for mRNA studies showing no damaging splice effect. This variant has a SpliceAI maximum delta score of 0.96 and RNA studies showed retention of 10 nucleotides of intron 19, so BP7 is not met. Details ▾Hide ▴

Rule

ENIGMA BP7 applies to no-impact splicing predictions or benign mRNA assay results.

Evidence considered

SpliceAI max delta score 0.96
RNA studies reported intron 19 retention

Sources

cspec ↗spliceai ↗vcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:21394826 ↗PMID:21673748 ↗

Not assessed · 6 · no assessment recorded

PS1 No evidence was identified that this variant is predicted to produce the same protein change or the same splice consequence as a different previously classified pathogenic or likely pathogenic BRCA1 variant under ENIGMA PS1 rules. Details ▾Hide ▴

Rule

ENIGMA PS1 variable-weight rule for same protein or splice consequence as a previously classified variant.

Evidence considered

ENIGMA PS1 requires the same protein or splice consequence as a previously classified variant.

Still missing

No structured reference-variant match for PS1 was available in the retrieved materials.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PS4 No case-control study showing a statistically increased prevalence of this variant in affected individuals versus controls was identified. Details ▾Hide ▴

Rule

ENIGMA PS4 requires p-value <=0.05 and odds ratio >=4 with lower confidence interval excluding 2.0.

Evidence considered

ENIGMA PS4 requires case-control evidence.

Still missing

No qualifying case-control data were retrieved.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PM3 No evidence was identified that this variant was observed in trans with another BRCA1 pathogenic variant in an individual with BRCA1-related Fanconi anemia. Details ▾Hide ▴

Rule

ENIGMA PM3 variable-weight rule for recessive BRCA1/2-related Fanconi anemia.

Evidence considered

ENIGMA PM3 is restricted to BRCA1/2-related Fanconi anemia.

Still missing

No recessive Fanconi anemia case-level data were retrieved.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP1 No quantitative co-segregation data were identified for this variant. Details ▾Hide ▴

Rule

ENIGMA PP1 uses likelihood-ratio-based segregation thresholds.

Evidence considered

ENIGMA PP1 requires quantitative segregation evidence.

Still missing

No family segregation likelihood ratio was retrieved.

Sources

cspec ↗PMID:17924331 ↗vcep_pmid_17924331_easton_2007_ajhgvcep_specifications_v1_2_2024_11_18

BS2 No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2. Details ▾Hide ▴

Rule

ENIGMA BS2 variable-weight rule for absence of BRCA1/2-related Fanconi anemia features.

Evidence considered

ENIGMA BS2 uses point-based unaffected observations in the recessive disease context.

Still missing

No qualifying BS2 point-based observations were retrieved.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BS4 No quantitative evidence for lack of segregation in affected family members was identified for this variant. Details ▾Hide ▴

Rule

ENIGMA BS4 uses likelihood-ratio-based non-segregation thresholds.

Evidence considered

ENIGMA BS4 requires quantitative non-segregation evidence.

Still missing

No family-based non-segregation likelihood ratio was retrieved.

Sources

cspec ↗PMID:17924331 ↗vcep_pmid_17924331_easton_2007_ajhgvcep_specifications_v1_2_2024_11_18

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS2 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

PS2 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PS3 N/AAvailable functional evidence is from mRNA splicing studies rather than protein-function assays. Under the ENIGMA BRCA1/2 specification, damaging mRNA-only evidence is applied under PVS1 (RNA) rather than PS3. Details ▾Hide ▴

Rule

mRNA-only damaging assay evidence is captured under PVS1 (RNA), not PS3.

Evidence considered

mRNA-only splicing studies showed aberrant transcripts.
ENIGMA routes mRNA-only damaging evidence to PVS1 RNA.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:21394826 ↗PMID:21673748 ↗

PM1 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

PM1 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PM4 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

PM4 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PM5 N/AThis intronic splice-region variant is not a protein-terminating variant eligible for ENIGMA PM5_PTC, and no qualifying missense PM5 scenario was identified. Details ▾Hide ▴

Rule

ENIGMA PM5_PTC applies to qualifying protein-terminating variants.

Evidence considered

PM5_PTC applies to protein termination codon variants annotated as PVS1.

Sources

cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

PM6 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

PM6 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP2 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

PP2 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP3 N/ASpliceAI predicts a strong splice effect for this variant (max delta score 0.96, above the ENIGMA PP3 threshold of 0.2), but ENIGMA specifies that PP3 should not be applied when PVS1 is met at any strength. Details ▾Hide ▴

Rule

Do not apply PP3 if PVS1 is met at any strength.

Evidence considered

SpliceAI max delta score 0.96
PVS1 was met

Sources

cspec ↗spliceai ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

BS3 N/AAvailable functional evidence is from mRNA splicing studies rather than protein-function assays showing no damaging effect. Under the ENIGMA BRCA1/2 specification, benign mRNA-only evidence is applied under BP7 rather than BS3. Details ▾Hide ▴

Rule

mRNA-only benign assay evidence is captured under BP7, not BS3.

Evidence considered

No benign protein-function assay evidence was identified.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP1 N/AThis is an intronic splice-region variant, not a silent, missense, or in-frame protein-coding variant eligible for BP1. Details ▾Hide ▴

Rule

ENIGMA BP1_Strong applies to selected coding variants outside functional domains with SpliceAI <=0.1.

Evidence considered

BP1 applies to silent
missense
or in-frame variants without predicted splice impact.

Sources

cspec ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

BP2 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

BP2 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP3 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

BP3 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP6 N/AThis criterion is not applicable in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴

Evidence considered

BP6 is marked not applicable in the BRCA1 specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

Identifiers

Gene: BRCA1
Transcript: NM_007294.4
Coding (HGVS c.): NM_007294.4:c.5194-12G>A
Protein (HGVS p.): NP_009225.1:p.?
GRCh38: chr17:43057147 C>T
GRCh37: chr17:41209164 C>T

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

	Protein	Location	Classification	Link

gnomAD v4.1 2 / 1,612,068 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,612,068 alleles · 0 hom · FAF 2.8e-07

European (non-Finnish)2 / 1,178,278

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= 1.24064e-06; MAF= 0.00012%, 2/1612068 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69739e-06; MAF= 0.00017%, 2/1178278 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

ENIGMA BP4 requires SpliceAI <=0.1 for eligible intronic variants.

Evidence considered

SpliceAI max delta score 0.96

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Rule

ENIGMA BP7 applies to no-impact splicing predictions or benign mRNA assay results.

Evidence considered

SpliceAI max delta score 0.96
RNA studies reported intron 19 retention

Sources

cspec ↗spliceai ↗vcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:21394826 ↗PMID:21673748 ↗

Rule

Do not apply PP3 if PVS1 is met at any strength.

Evidence considered

SpliceAI max delta score 0.96
PVS1 was met

Sources

cspec ↗spliceai ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 2 / 1,612,068 recorded alleles Open source ↗

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

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC 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.

ClinVar

This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).