Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4485-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43074522-C-A is Pathogenic according to our data. Variant chr17-43074522-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 246501.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:2
Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.997462 -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
not providedPathogenic:2
Jan 01, 2020
GeneKor MSA
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This mutation occurs one base before exon 14 of the BRCA1 gene. This position is highly conserved in the human and other genomes and might be involved in mRNA processing. Therefore, this mutation is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is also known as IVS13-1G>T or 4604-1G>T in the literature and it has been reported in a patient with high grade serous ovarian cancer(PMID: 26622941 ). The mutation database ClinVar contains entries for this variant (Variation ID: 246501). -
Jan 19, 2021
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Fleury 2015); Not observed in large population cohorts (Lek 2016); Also known as 4604-1G>T (IVS14-1G>T); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26622941, 29446198, 31131967) -
Hereditary breast ovarian cancer syndromePathogenic:2
Jan 27, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.4485-1G>T variant in BRCA1 has been reported in 1 French Canadian individu al with BRCA1-associated cancer (Fleury 2015). It was absent from large populati on studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abno rmal or absent protein. Consistent with this prediction, in vitro functional stu dies demonstrate altered splicing and no appreciable protein expression in cells that harbor this variant in the homozygous state (Fleury 2015). In summary, the c.4485-1G>T variant meets criteria to be classified as pathogenic for hereditar y breast and ovarian cancer (HBOC) in an autosomal dominant manner based upon it s predicted impact to the protein and functional studies. -
Jun 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change affects an acceptor splice site in intron 13 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 12181777, 26622941, 27553291, 29446198, 34026625). ClinVar contains an entry for this variant (Variation ID: 246501). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 26622941). For these reasons, this variant has been classified as Pathogenic. -
The c.4485-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 13 of the BRCA1 gene. This alteration has been reported in a patient with high-grade serous epithelial ovarian cancer (EOC). In vivo studies conducted in an EOC cell line homozygous for this alteration identified the presence of a novel transcript induced by abnormal splicing, resulting in the absence of BRCA1 protein (Fleury H et al. Genes Cancer, 2015 Sep;6:378-398). This alteration has been reported in a large, worldwide study of BRCA1 and BRCA2 mutation carriers (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). This alteration was also identified in 2/50726 patients from an unselected population cohort from a single health system who underwent exome sequencing (Manickam K et al. JAMA Netw Open, 2018 09;1:e182140). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -