BRCA1c.68_69delPathogenic

Print report

Variant interpretation report

BRCA1 c.68_69del, p.(Glu23ValfsTer17)

NM_007294.3:c.68_69del NP_009225.1:p.(Glu23ValfsTer17) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A 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 supporting (benign) · 2 very strong (pathogenic) · 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen BRCA1 VCEP v1.2.0
Other laboratories (ClinVar): 79 Pathogenic
Pipeline record: 18 May 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This variant is a 2-bp deletion in BRCA1 exon 2 that causes an early frameshift, NP_009225.1:p.(Glu23ValfsTer17) (p.(E23Vfs*17)), with a premature termination codon. Loss of function is an established disease mechanism for BRCA1, and the ENIGMA BRCA1 specification assigns PVS1 to exon 2 protein-truncating variants.
PM5 (strong): In the ENIGMA BRCA1 framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense comparison. This frameshift creates a premature termination codon in BRCA1 exon 2, and ENIGMA Table 4 and Supplementary Table 1 assign PM5_Strong for exon 2 protein-truncating variants.
PP4 (very strong): In the BRCA1 clinical-history likelihood-ratio dataset, this variant is listed as c.68_69delAG in 202 probands with LR 1.145935772193482e+20. This value is far above the ENIGMA PP4 Very Strong threshold of 350, supporting a strong pathogenic clinical-history signal.
PP5 (supporting): Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
BS1 (supporting): The non-founder filter allele frequency is above the ENIGMA BS1 Supporting threshold of 0.00002 and does not exceed the BS1 Strong threshold of 0.0001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, so BS1 is met at Supporting strength.

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: 4 Benign evidence criteria: 1

Pathogenic criteria applied · 4

PVS1Very strong

PVS1 · very strong

This variant is a 2-bp deletion in BRCA1 exon 2 that causes an early frameshift, NP_009225.1:p.(Glu23ValfsTer17) (p.(E23Vfs*17)), with a premature termination codon. Loss of function is an established disease mechanism for BRCA1, and the ENIGMA BRCA1 specification assigns PVS1 to exon 2 protein-truncating variants.

PM5Strong

PM5 · strong

In the ENIGMA BRCA1 framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense comparison. This frameshift creates a premature termination codon in BRCA1 exon 2, and ENIGMA Table 4 and Supplementary Table 1 assign PM5_Strong for exon 2 protein-truncating variants.

PP4Very strong

PP4 · very strong

In the BRCA1 clinical-history likelihood-ratio dataset, this variant is listed as c.68_69delAG in 202 probands with LR 1.145935772193482e+20. This value is far above the ENIGMA PP4 Very Strong threshold of 350, supporting a strong pathogenic clinical-history signal.

PP5Supporting

PP5 · supporting

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

Benign criteria applied · 1

BS1Supporting

BS1 · supporting

The non-founder filter allele frequency is above the ENIGMA BS1 Supporting threshold of 0.00002 and does not exceed the BS1 Strong threshold of 0.0001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, so BS1 is met at Supporting strength.

Recorded classification: Pathogenic

ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 with ENIGMA conflicting-evidence point system).

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

191 / 1,612,084 alleles

gnomAD v4.1: 191 / 1,612,084 alleles. Recorded AF 0.00011848. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000205352; MAF= 0.02054%, 58/282442 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00405093; MAF= 0.40509%, 42/10368 alleles, homozygotes = 0); grpmax FAF= 5.395e-05.

Applied · BS1 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

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

79 reported laboratory submissions

79 Pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

5 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV58786277, n = 5 times).

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.

28 criteria with recorded statuses: 5 met · 3 not met · 5 not assessed · 15 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 NM_007294.3:c.68_69del (NP_009225.1:p.(Glu23ValfsTer17); p.(E23Vfs*17)) variant has been reported in ClinVar as Pathogenic with expert-panel review and is also curated in OncoKB as a loss-of-function BRCA1 variant.

In gnomAD, the variant is present overall at AF 0.000205352 in v2.1 and 0.00011848 in v4.1, with non-founder grpmax FAF values of 5.395e-05 and 2.478e-05 respectively; this is above the ENIGMA BS1 Supporting threshold of 0.00002 but below the BA1 threshold of 0.001.

This 2-bp deletion causes an early frameshift with a predicted premature stop, and the ENIGMA BRCA1 specification assigns PVS1 for exon 2 truncating variants and PM5_Strong for protein-truncating variants in exon 2.

BRCA1 clinical-history likelihood analysis lists the equivalent c.68_69delAG variant in 202 probands with LR 1.145935772193482e+20, far above the ENIGMA PP4 Very Strong threshold of 350.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which does not create a separate PP3 or BP4 code for this protein-truncating frameshift under the ENIGMA BRCA1 rules.

Met · 5

PVS1 Very strongThis variant is a 2-bp deletion in BRCA1 exon 2 that causes an early frameshift, NP_009225.1:p.(Glu23ValfsTer17) (p.(E23Vfs*17)), with a premature termination codon. Loss of function is an established disease mechanism for BRCA1, and the ENIGMA BRCA1 specification assigns PVS1 to exon 2 protein-truncating variants. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PVS1 for null variants, with exon-specific weighting from Table 4.

Evidence considered

BRCA1 loss of function is established in the applicable ENIGMA framework.
The variant is a frameshift with predicted p.(Glu23ValfsTer17).
ENIGMA Table 4 assigns PVS1 to BRCA1 exon 2 protein-truncating variants.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

PM5 StrongIn the ENIGMA BRCA1 framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense comparison. This frameshift creates a premature termination codon in BRCA1 exon 2, and ENIGMA Table 4 and Supplementary Table 1 assign PM5_Strong for exon 2 protein-truncating variants. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PM5_PTC exon-specific rule for truncating variants.

Evidence considered

PM5 candidate artifact indicates gene-specific PTC logic rather than classic same-residue PM5.
ENIGMA Table 4 lists BRCA1 exon 2 PTC variants as PM5_Strong (PTC).
Supplementary Table 1 shows Strong PM5_PTC weighting for BRCA1 exon 2.

Sources

cspec ↗pm5_candidatesvcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

PP4 Very strongIn the BRCA1 clinical-history likelihood-ratio dataset, this variant is listed as c.68_69delAG in 202 probands with LR 1.145935772193482e+20. This value is far above the ENIGMA PP4 Very Strong threshold of 350, supporting a strong pathogenic clinical-history signal. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PP4 uses LR-based clinical-history thresholds.

Evidence considered

Clinical-history LR workbook contains BRCA1 c.68_69delAG.
Observed LR is 1.145935772193482e+20 in 202 probands.
ENIGMA PP4 Very Strong threshold is LR >= 350.

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 ▴

Rule

ENIGMA BRCA1 specification marks PP5 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗vcep_specifications_v1_2_2024_11_18

BS1 SupportingThe non-founder filter allele frequency is above the ENIGMA BS1 Supporting threshold of 0.00002 and does not exceed the BS1 Strong threshold of 0.0001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, so BS1 is met at Supporting strength. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BS1 Supporting requires non-founder FAF > 0.00002 and <= 0.0001.

Evidence considered

gnomAD v2.1 grpmax FAF 5.395e-05.
gnomAD v4.1 grpmax FAF 2.478e-05.
Both values are >0.00002 and <=0.0001.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18

Not met · 3 · evaluated, threshold not reached

PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.000205352 (58/282442) and in gnomAD v4.1 at AF 0.00011848 (191/1612084), so the ENIGMA PM2 requirement for absence from controls is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PM2_Supporting requires absence from controls in gnomAD with adequate coverage.

Evidence considered

Variant observed in gnomAD v2.1.
Variant observed in gnomAD v4.1.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18

BA1 The non-founder filter allele frequency does not exceed the ENIGMA BA1 threshold of 0.001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, both below the BA1 threshold. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BA1 requires non-founder FAF > 0.001.

Evidence considered

gnomAD v2.1 grpmax FAF 5.395e-05.
gnomAD v4.1 grpmax FAF 2.478e-05.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18

BP5 The available clinical-history likelihood evidence is strongly in the pathogenic direction rather than the benign direction. The observed LR for c.68_69delAG is 1.145935772193482e+20, which is far above the ENIGMA benign BP5 thresholds of 0.48, 0.23, 0.05, and 0.00285, so BP5 is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BP5 uses LR-based clinical-history thresholds in the benign direction.

Evidence considered

Clinical-history LR is 1.145935772193482e+20 in 202 probands.
BP5 requires LR at or below benign thresholds.

Sources

cspec ↗PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr

Not assessed · 5 · no assessment recorded

PS4 This variant has been reported as pathogenic in ClinVar, but no directly extracted case-control odds ratio or p-value meeting the ENIGMA PS4 thresholds was identified in the reviewed sources. Available evidence supports clinical importance, but PS4 was not formally established from the materials reviewed here. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PS4 requires significantly increased prevalence in affected individuals versus controls with specified statistical thresholds.

Evidence considered

ClinVar expert-panel pathogenic classification was identified.
No reviewed source provided the required PS4 case-control statistics.

Still missing

Direct case-control counts
odds ratio
confidence interval
and p-value were not extracted from reviewed sources.
An ancestry-matched comparison using the ENIGMA PS4 framework would still require manual confirmation.

Sources

clinvar ↗cspec ↗vcep_specifications_v1_2_2024_11_18

PM3 ENIGMA applies PM3 in the setting of BRCA1- or BRCA2-related Fanconi anemia with qualifying biallelic observations. No such proband-level recessive disease evidence was identified for this variant. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PM3 is specific to Fanconi anemia-related biallelic observations.

Evidence considered

No recessive disease data were identified.

Still missing

No Fanconi anemia phenotype or qualifying biallelic observations were identified.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP1 No quantitative segregation analysis or likelihood ratio meeting the ENIGMA PP1 thresholds was identified for this variant in the reviewed sources. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PP1 requires quantitative cosegregation evidence with LR-based thresholds.

Evidence considered

No segregation dataset or calculated LR was identified.

Still missing

No pedigree-based segregation likelihood ratio was identified.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BS2 ENIGMA applies BS2 using point-based observations in individuals without Fanconi anemia features. No qualifying proband-level data were identified for this variant in the reviewed sources. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BS2 requires point-based qualifying observations.

Evidence considered

No qualifying unaffected/recessive-disease-negative observations were identified.

Still missing

No BS2 point-based observations were identified.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BS4 No quantitative non-segregation analysis meeting the ENIGMA BS4 thresholds was identified for this variant in the reviewed sources. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BS4 requires quantitative lack-of-segregation evidence with LR-based thresholds.

Evidence considered

No quantified non-segregation evidence was identified.

Still missing

No pedigree-based non-segregation likelihood ratio was identified.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/AThis criterion applies to predicted missense substitutions or variants with the same predicted splicing effect as a previously classified pathogenic variant. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PS1 applies to missense or matched splicing-effect comparisons.

Evidence considered

Variant type is frameshift.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PS2 VCEPPS2 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks PS2 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PS3 N/AThe curated ENIGMA functional assay tables are designed for missense and synonymous variants. No variant-specific calibrated protein functional study assignment was identified for this frameshift deletion, so PS3 is not applicable here. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PS3 uses calibrated functional studies, primarily via Table 9.

Evidence considered

Table 9 is curated for missense and synonymous variants.
The variant is a frameshift deletion.

Sources

cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

PM1 VCEPPM1 is not used in this ENIGMA BRCA1 specification for this variant context. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks PM1 not applicable.

Evidence considered

Criterion listed as not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PM4 VCEPPM4 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks PM4 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PM6 VCEPPM6 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks PM6 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP2 VCEPPP2 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks PP2 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

PP3 N/AENIGMA PP3 computational evidence is applied to missense, in-frame, silent, or relevant intronic variants. This variant is a protein-truncating frameshift deletion, so PP3 is not applicable as a separate criterion. Details ▾Hide ▴

Rule

ENIGMA BRCA1 PP3 applies to defined non-truncating variant classes or predicted splice effects outside canonical null-variant handling.

Evidence considered

Variant type is frameshift.
SpliceAI max delta score is 0.00
but ENIGMA PP3 rules do not create a separate PP3 code for this truncating variant type.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

BS3 N/AThe curated ENIGMA functional assay framework for BS3 is directed to missense and synonymous variants. No calibrated benign functional assay assignment was identified for this frameshift deletion, so BS3 is not applicable here. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BS3 uses calibrated functional studies, primarily via Table 9.

Evidence considered

Table 9 is curated for missense and synonymous variants.
The variant is a frameshift deletion.

Sources

cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

BP1 N/ABP1 in the ENIGMA BRCA1 framework applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This variant is a frameshift deletion, so BP1 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BP1 applies only to defined non-truncating variant classes.

Evidence considered

Variant type is frameshift.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP2 VCEPBP2 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks BP2 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP3 VCEPBP3 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks BP3 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP4 N/AENIGMA BP4 computational evidence is applied to selected missense, in-frame, silent, and intronic variants without predicted impact. This variant is a protein-truncating frameshift deletion, so BP4 is not applicable as a separate criterion. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BP4 applies to defined non-truncating variant classes.

Evidence considered

Variant type is frameshift.
SpliceAI max delta score is 0.00
but ENIGMA BP4 rules do not create a separate BP4 code for this truncating variant type.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

BP6 VCEPBP6 is not used in this ENIGMA BRCA1 specification. Details ▾Hide ▴

VCEP rule

ENIGMA BRCA1 specification marks BP6 not applicable.

Evidence considered

Criterion marked not applicable in the BRCA1 ENIGMA specification.

Sources

cspec ↗vcep_specifications_v1_2_2024_11_18

BP7 N/ABP7 in the ENIGMA BRCA1 framework applies to silent or intronic variants, or selected non-truncating variants with RNA evidence. This variant is a frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴

Rule

ENIGMA BRCA1 BP7 applies to silent, intronic, or defined non-truncating variants.

Evidence considered

Variant type is frameshift.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Identifiers

Gene: BRCA1
Transcript: NM_007294.3
Coding (HGVS c.): NM_007294.3:c.68_69del
Protein (HGVS p.): NP_009225.1:p.(Glu23ValfsTer17)
GRCh38: chr17:43124027 ACT>A
GRCh37: chr17:41276044 ACT>A
ClinVar: 17662
COSMIC: COSV58786277

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.3. Select a row to find it on the plot.

BRCA1NM_007294.3

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 v4.1 191 / 1,612,084 alleles AF 0.000118 · 0 homozygotes · FAF 2.48e-05

gnomAD v2.1 58 / 282,442 alleles AF 0.000205 · 0 homozygotes · FAF 5.39e-05

By genetic ancestry

gnomAD v4.1

AF 0.00012 · 191 / 1,612,084 alleles · 0 hom · FAF 2.5e-05

Ashkenazi Jewish123 / 29,578	0.0042
Remaining individuals20 / 62,394	0.00032
Middle Eastern1 / 6,078	0.00016
South Asian5 / 91,044	5.5e-05
Admixed American3 / 59,996	5e-05
European (non-Finnish)39 / 1,178,366	3.3e-05

0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, African/African American.

gnomAD v2.1

AF 0.00021 · 58 / 282,442 alleles · 0 hom · FAF 5.4e-05

Ashkenazi Jewish42 / 10,368	0.0041
South Asian4 / 30,608	0.00013
European (non-Finnish)11 / 128,780	8.5e-05
Admixed American1 / 35,440	2.8e-05

0 alternate alleles recorded in 4 other groups: African/African American, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00011848; MAF= 0.01185%, 191/1612084 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0041585; MAF= 0.41585%, 123/29578 alleles, homozygotes = 0); grpmax FAF= 2.478e-05.

gnomAD v2.1

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

ENIGMA BRCA1 PP3 applies to defined non-truncating variant classes or predicted splice effects outside canonical null-variant handling.

Evidence considered

Variant type is frameshift.
SpliceAI max delta score is 0.00
but ENIGMA PP3 rules do not create a separate PP3 code for this truncating variant type.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Rule

ENIGMA BRCA1 BP4 applies to defined non-truncating variant classes.

Evidence considered

Variant type is frameshift.
SpliceAI max delta score is 0.00
but ENIGMA BP4 rules do not create a separate BP4 code for this truncating variant type.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Rule

ENIGMA BRCA1 BP7 applies to silent, intronic, or defined non-truncating variants.

Evidence considered

Variant type is frameshift.

Sources

cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.

No paper-specific finding is recorded.

PMID 14576434 ↗
A high-throughput functional complementation assay for classification of BRCA1 missense variants.

No paper-specific finding is recorded.

PMID 23867111 ↗
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

No paper-specific finding is recorded.

PMID 9145676 ↗
Cytoplasmic mislocalization of BRCA1 caused by cancer-associated mutations in the BRCT domain.

No paper-specific finding is recorded.

PMID 14729053 ↗
The BRCA1 RING and BRCT domains cooperate in targeting BRCA1 to ionizing radiation-induced nuclear foci.

No paper-specific finding is recorded.

PMID 15569676 ↗
Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.

No paper-specific finding is recorded.

PMID 26246475 ↗
BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.

No paper-specific finding is recorded.

PMID 27454287 ↗
The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.

No paper-specific finding is recorded.

PMID 11466700 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.

No paper-specific finding is recorded.

PMID 30122538 ↗

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

gnomAD v4.1 191 / 1,612,084 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 79 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

ClinVar

This variant has been reported in ClinVar as Pathogenic (79 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 17662)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58786277, n = 5 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.