Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4986+5G>A variant causes a splice region, intron change. 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 Likely 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]
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43070923-C-T is Pathogenic according to our data. Variant chr17-43070923-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 96936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43070923-C-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Uncertain:1Other:1
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jan 24, 2011
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
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Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Mar 25, 2013
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 30, 2019
For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 23239986, 23451180, 30209399). This variant has been observed in an individual affected with breast cancer (PMID: 23239986). ClinVar contains an entry for this variant (Variation ID: 96936). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Dec 21, 2017
Variant summary: The BRCA1 c.4986+5G>A variant (alternatively known as IVS16+5G>A and 5105+5G>A) involves the alteration of a conserved intronic nucleotide and is predicted to impact splicing by 4/5 splice prediction tools. Mutation taster also predicts a damaging outcome for this variant. This variant is absent in 244498 control chromosomes (gnomAD). This variant has been reported in breast and pancreatic cancer patients in the literature (Wappenschmidt_2012, Mandelker_2017) and functional studies show that it leads to the retention of 65 nucleotides of the 5' end of intron 15 which leads to premature truncation of the BRCA1 protein (p.Met1663Valfs*14) (Wappenschmidt_2012, Colombo_2013). Other similar variants (c.4986+3G>C, c.4986+4A>G, c.4986+5G>T and c.4986+6T>C) were found to cause the incorporation of the 65 intronic nucleotides [Wappenschmidt_2012, Vreeswijk_2009 (PMID: 18693280)]. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic. -
Familial cancer of breast Pathogenic:1
Likely pathogenic, no assertion criteria provided
literature only
Center for Precision Medicine, Meizhou People's Hospital
The c.4986+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 14 in the BRCA1 gene. This alteration was identified in a cohort of Chinese ovarian cancer patients (Deng H et al. Mol Genet Genomic Med. 2019 Jun;7:e672). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration has been shown to lead to retention of 65 nucleotides of the affected intron leading to a predicted frameshift (Ambry internal data; Colombo M et al. PLoS ONE, 2013 Feb;8:e57173; Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800). This alteration was also shown to be non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Similar alterations have also been shown to lead to the same splice defect (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71; Vreeswijk MP et al. Hum. Mutat., 2009 Jan;30:107-14). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Breast carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided
clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Aug 24, 2021
Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 70% -