BRCA1 c.427G>T, p.Glu143Ter
NM_007294.4:c.427G>T
Pathogenic
This variant introduces a premature stop codon in BRCA1, a gene intolerant of loss-of-function. PVS1 (Very Strong), PS3 (Strong), PM2 (Supporting) and PP5 (Supporting) lead to a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.427G>T
Protein Change
E143*
Location
Exon 6
(Exon 6 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.427G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
10 publications
Pathogenic
Based on 25 submitter reviews in ClinVar
Submitter Breakdown
24 Path
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (10)
The p.Glu143X variant in BRCA1 has been reported in >15 individuals with BRCA1-related cancers (Shattuck-Eidens 1997, Caligo 2009, Cunningham 2014, Susswein 2016, Lowery 2018, Yurgelun 2019, BIC database). It was absent from large population studies. This frameshift variant leads to a premature termination codon at position 143, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
The BRCA1 c.427G>T (p.Glu143*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals affected with breast cancer (PMID: 27836010 (2016), 23961350 (2012), 22009639 (2012), 20104584 (2010)) and ovarian cancer (PMID: 36169650 (2022), 24504028 (2014)) as well as individuals with prostate cancer (PMID: 32338768 (2020)) and pancreatic cancer (PMID: 29961768 (2019), 29506128 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
This sequence change creates a premature translational stop signal (p.Glu143*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 20104584, 22009639, 23961350, 24504028). This variant is also known as 546G>T and E143X. ClinVar contains an entry for this variant (Variation ID: 37581). For these reasons, this variant has been classified as Pathogenic.
Variant summary: BRCA1 c.427G>T (p.Glu143X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251024 control chromosomes. c.427G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Solano_2013, Judkins_2005, Evans_2003, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (24 clinical laboratories) and as pathogenic (1 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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
Functional Summary
The BRCA1 E143* variant is a truncating mutation that has been functionally characterized as likely causing loss of function. Truncating mutations in BRCA1 can lead to aberrant protein folding and impaired DNA damage response, as evidenced by elevated aneuploidy levels in human breast cancer cell lines. Additionally, mouse models with BRCA1 truncating mutations develop various cancers, supporting the damaging effect of such mutations.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 5.59
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: "Very Strong Strength: 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: NM_007294.4:c.427G>T introduces a premature stop codon (p.Glu143*) leading to predicted LOF in BRCA1, a gene with established LOF disease mechanism. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a LOF disease gene and not in the last exon.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change..." The evidence for this variant shows: c.427G>T is a nonsense change, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no reported de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines: "Strong Strength: Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional assays in human cell lines and mouse models demonstrate loss of BRCA1 function for truncating variants like p.Glu143*. Therefore, this criterion is applied at Strong strength because well-established functional data support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: The prevalence of the variant in affected individuals is significantly increased compared to controls (p ≤0.05 and OR ≥4)." The evidence for this variant shows: no published case‐control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "PM1: Located in a mutational hot spot or well‐studied functional domain without benign variation." The evidence for this variant shows: p.Glu143* is a truncating change, not a domain missense hotspot. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting Strength: Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The evidence for this variant shows: the variant is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the allele is not observed in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "PM3: Detected in trans with a pathogenic variant in patients with a recessive phenotype (e.g., Fanconi Anemia)." The evidence for this variant shows: no data on co-occurrence in Fanconi Anemia. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM4: Protein length changes due to in‐frame deletions/insertions in non‐repeat regions or stop‐loss." The evidence for this variant shows: this is a nonsense variant causing truncation, covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "PM5_PTC: Protein termination codon variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: exon‐specific counts of known pathogenic PTC variants are not provided. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM6: Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "PP1: Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2: Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "PP3: In silico predictions supporting a deleterious effect." The evidence for this variant shows: truncating variants do not require computational prediction. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: "PP4: Patient phenotype highly specific for a disease with single genetic etiology." The evidence for this variant shows: no specific phenotype reported. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "PP5: Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory." The evidence for this variant shows: ClinVar entries include 24 pathogenic classifications and ENIGMA expert panel designation. Therefore, this criterion is applied at Supporting strength because multiple reputable sources report pathogenicity without accessible primary evidence.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1: Allele frequency >0.1% in gnomAD non-cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1: Filter allele frequency >0.01% in gnomAD non-cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "BS2: Observed in healthy adult individuals incompatible with a recessive phenotype (Fanconi Anemia)." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3: Well-established functional studies showing no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "BS4: Lack of segregation in affected members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: "BP1: Missense variant in a gene for which primarily truncating variants are pathogenic." The evidence for this variant shows: this is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP2: Observed in cis with a pathogenic variant." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3: In‐frame deletions/insertions in repetitive region." The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "BP4: In silico predictions supporting benign impact." The evidence for this variant shows: not relevant for truncating variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "BP5: Co-occurrence with pathogenic variant in another gene." The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP6: Reputable source reports variant as benign without evidence." The evidence for this variant shows: not reported benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "BP7: Synonymous variant without splicing impact or intronic outside splice sites." The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.