Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1390_1391insG(p.Thr464SerfsTer16) 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. T464T) has been classified as 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]
Verdict is Pathogenic. Variant got 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 17-43094140-G-GC is Pathogenic according to our data. Variant chr17-43094140-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 54235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
- -
Apr 20, 2017
Department of Pathology and Molecular Medicine, Queen's University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jul 21, 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.Thr464Serfs*16) 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 cancer and/or ovarian cancer (PMID: 11933205, 17148771). This variant is also known as 1510insG. ClinVar contains an entry for this variant (Variation ID: 54235). For these reasons, this variant has been classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Feb 23, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Malignant tumor of breast Pathogenic:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
The BRCA1 p.Thr464Serfs*16 variant was identified in 2 of 5026 proband chromosomes (frequency: 0.0004) from individuals or families with ovarian cancer (Risch 2006, Zhang 2011) and in two Canadian families of aboriginal descent both with the same BRCA1 alterations (1510insG, 1506A>G)( Liede 2002). The variant was also identified in dbSNP (ID: rs397508867) as "With Pathogenic allele", ClinVar (classified as pathogenic by COGR). The variant was not identified in LOVD 3.0 and UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1390_1391insG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 464 and leads to a premature stop codon at position 479. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in BRCA1 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1510insG in the literature. This variant also has been observed in cis with c.1387A>G (1506A>G) (PMID: 11933205). The two in cis variants, c.1387A>G and c.1390_1391insG, may be described together as 1506del4ins5 or c.1387_1390delinsGAAAG (ClinVar variation ID: 54234). This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast and ovarian cancer (PMID: 11933205, 17148771, 21324516; Color internal data). This variant has not been identified 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. -