Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1912delG(p.Glu638AsnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E638E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43093618-TC-T is Pathogenic according to our data. Variant chr17-43093618-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 54398.Status of the report is reviewed_by_expert_panel, 3 stars.
The c.1912delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1912, causing a translational frameshift with a predicted alternate stop codon (p.E638Nfs*13). This mutation has been reported in multiple breast and/or ovarian cancer families (Díez O et al. Hum Mutat, 2003 Oct;22:301-12; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Palmero EI et al. Sci Rep, 2018 06;8:9188). Of note, this alteration is also designated as 2031delG in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Mar 02, 2025
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PVS1, PM5_PTC_Strong c.1912del, located in exon 10 (11 according BIC nomenclature) of the BRCA1 gene, consists in the deletion of 1 nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(Glu638Asnfs*13). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset. No effect is predicted on splicing by computational tools. To our knowledge, no functional studies have been reported for this variant. This variant has been repeatedly reported in breast and ovarian cancer families. In addition, it has been reported in ClinVar (6x pathogenic and 1x pathogenic and reviewed by an expert panel: ENIGMA (8/9/2016): ”Variant allele predicted to encode a truncated non-functional protein”), and LOVD databases (11x pathogenic). Based on currently available information, the variant c.1912del should be considered a pathogenic variant. -
not providedPathogenic:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Familial cancer of breastPathogenic:1
Feb 23, 2017
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:1
Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Glu638Asnfs*13) 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: 12955716, 27741520, 28477318, 29021639). This variant is also known as 2031delG and c.1912_1912del. ClinVar contains an entry for this variant (Variation ID: 54398). For these reasons, this variant has been classified as Pathogenic. -