Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2241dupC(p.Lys748fs) 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 (★★★). 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 17-43093289-T-TG is Pathogenic according to our data. Variant chr17-43093289-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 54511.Status of the report is reviewed_by_expert_panel, 3 stars.
This variant duplicates 1 nucleotide in exon 10 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. To our knowledge, this variant has been reported in one individual affected with breast, ovary and colon cancer (PMID: 20567915) and one individual referred to BRCA1/2 genetic test (PMID: 28263838). 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. -
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneKor MSA
Jan 01, 2020
This sequence change is an insertion of 1 nucleotide in exon 11 of BRCA1 mRNA (c.2241dupC), causing a frameshift after codon 748 and the creation of a premature translation stop signal 14 amino acid residues later (p.Lys748Glnfs*14). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular variant has been described in the international bibliography in an individual with a personal and family history of breast and/or ovarian cancer (PMID: 20567915) and listed in the mutation database ClinVar (Variation ID: 54511) -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 06, 2016
For these reasons, this variant has been classified as Pathogenic. This sequence change inserts 1 nucleotide in exon 10 of the BRCA1 mRNA (c.2241dupC), causing a frameshift at codon 748. This creates a premature translational stop signal (p.Lys748Glnfs*14) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in two siblings who developed multiple cancers, one with ovarian and breast cancer, and the other with ovarian and colon cancer (PMID: 20567915). -