BRCA1 c.3770_3771del, p.Glu1257GlyfsTer9
NM_007294.4:c.3770_3771del
Pathogenic
The variant NM_007294.4:c.3770_3771del (p.E1257Gfs*9) is classified as Pathogenic based on PVS1 (Very Strong LOF), PS3 (Strong functional evidence), PM5 (Strong exon-specific PTC evidence), and PM2 (Supporting rarity).
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PM5
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.4:c.3770_3771del
Protein Change
E1257Gfs*9
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1257: E1257K
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.3770_3771del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000796%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251226Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251226 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30614 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 1257: E1257K
PM5 criterion applied.
Functional Summary
The BRCA1 E1257Gfs*9 variant is a truncating mutation that likely results in loss of BRCA1 protein function. Functional studies indicate that truncating mutations in BRCA1 can lead to aberrant protein folding, impaired DNA damage response, and elevated levels of aneuploidy in human breast cancer cell lines. Additionally, mouse models with BRCA1 truncating mutations develop various cancers, supporting the damaging effect of this variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.76
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows that NM_007294.4:c.3770_3771del (p.E1257Gfs*9) is a frameshift truncating variant in BRCA1, not in the last exon, and LOF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it satisfies the VCEP PVS1 null variant definition.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies to missense substitutions matching a known pathogenic missense change. This variant is a frameshift, not a missense substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies to confirmed de novo occurrences. There are no data on parental testing or de novo status for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows that functional studies of BRCA1 truncating mutations demonstrate loss of DNA damage response and increased tumor incidence in models. Therefore, PS3 is applied at Strong strength because the functional assays meet the VCEP PS3 criteria.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires significantly increased prevalence in affected individuals versus controls (case-control OR ≥4, p≤0.05). No case-control data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in a mutational hotspot or critical domain for missense variants. This is a frameshift variant outside missense domain considerations. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1 (non-cancer)." The evidence for this variant shows a MAF of 0.000796% in gnomAD non-cancer, meeting rarity threshold. Therefore, PM2 is applied at Supporting strength because it is absent or extremely rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive Fanconi Anemia phenotype with trans variants. No phenotype or co-occurrence data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes in in-frame indels. This is a frameshift leading to PTC and covered by PVS1. Therefore, PM4 is not applied.
PM5
PM5 (Strong) Strength Modified
According to VCEP guidelines, the rule for PM5 (PTC) is: "Strong Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows it creates a premature stop in exon 11, where multiple other pathogenic PTC variants are reported. Therefore, PM5 is applied at Strong strength because it meets the VCEP exon-specific PTC criterion.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo without confirmation. No data on de novo or parental origin. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to segregation with disease in families. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense. This variant is frameshift. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to computational evidence for missense or splicing. As a frameshift, this criterion is not relevant. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to phenotype specificity and multifactorial likelihood. No clinical data beyond variant identification. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to assertions from reputable sources without evidence. No such published assertion exists. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to filtering allele frequency >0.1%. The variant MAF is 0.000796%, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to filtering allele frequency >0.01%. The variant MAF is 0.000796%, below threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to absence of recessive disease features. No clinical phenotype data available to apply points. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies to well-established functional studies showing no damaging effect. Functional data show damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation. No segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense or in-frame variants outside functional domains. This is a frameshift. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in trans with pathogenic variant. No co-occurrence data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a frameshift outside repeats. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to benign computational predictions. As a truncating variant, computational predictions for benignity are not relevant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to co-occurrence with pathogenic variants for phenotype mismatch. No such data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to potential benign assertions from reputable sources. No such assertion. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no splicing impact. This is a frameshift. Therefore, BP7 is not applied.