Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4182_4183dupTC(p.Gln1395LeufsTer11) variant causes a frameshift, splice region change. 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. Q1395Q) has been classified as Pathogenic. 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 17-43090945-T-TGA is Pathogenic according to our data. Variant chr17-43090945-T-TGA is described in ClinVar as Pathogenic. ClinVar VariationId is 55124.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:4
Dec 13, 2023
All of Us Research Program, National Institutes of Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant inserts 2 nucleotides in exon 11 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A frameshift mutation at this codon Gln1395 has been reported in an individual affected with ovarian cancer (PMID: 21990299). This variant has been identified in 1/242736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Nov 25, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein. -
The c.4182_4183dupTC pathogenic mutation, located in coding exon 10 of the BRCA1 gene, results from a duplication of 2 nucleotides at positions 4182 and 4183, causing a translational frameshift with a predicted alternate stop codon (p.Q1395Lfs*11). 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. -
Oct 18, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant inserts 2 nucleotides in exon 11 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A frameshift mutation at this codon Gln1395 has been reported in an individual affected with ovarian cancer (PMID: 21990299). This variant has been identified in 1/242736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not providedPathogenic:1
Nov 12, 2015
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This duplication of 2 nucleotides in BRCA1 is denoted c.4182_4183dupTC at the cDNA level and p.Gln1395LeufsX11 (Q1395LfsX11) at the protein level. The normal sequence, with the bases that are duplicated in braces, is CCAC[TC]AGgt, where the capital letters are exonic and lowercase are intronic. The duplication causes a frameshift, which changes a Glutamine to a Leucine at codon 1395, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.4182_4183dupTC, also reported as BRCA1 Q1395fs, has been observed in at least one woman with serous ovarian cancer (Yang 2011). We consider this variant to be pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Feb 08, 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.Gln1395Leufs*11) 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 present in population databases (rs80357742, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 21990299). ClinVar contains an entry for this variant (Variation ID: 55124). For these reasons, this variant has been classified as Pathogenic. -