Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.4986+6T>G 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 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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43070922-A-C is Pathogenic according to our data. Variant chr17-43070922-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 55344.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43070922-A-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8Other:2
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
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Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jul 23, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Sep 13, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Breast Cancer Information Core (BIC) (BRCA1)
Significance: not provided
Review Status: no classification provided
Collection Method: clinical testing
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Feb 05, 2019
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This c.4986+6T>G variant in the BRCA1 gene has been reported in multiple individuals affected with breast cancer or ovarian cancer (PMID 11179017, 16619214, 21913181, 22160602) and is extremely rare in general population databases. An RT-PCR assay using mRNA derived from an affected individual showed 65bp insertion, which is predicted to introduce a premature translation termination codon (PMID 16619214). Therefore, the c.4986+6T>G variant in the BRCA1 gene is classified as pathogenic. -
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 = 0.999999 -
Aug 28, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes a T>G nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant is also known as 5105+6T>G and IVS16+6T>G in the literature. RNA studies on carrier-derived RNA (PMID: 16619214) and in a mini-gene splicing assay (PMID: 24667779) have found this variant to disrupt splicing in a manner that is expected to result in an absent or non-functional protein product. This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals with personal and/or family history of breast and ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). This variant also has been reported as pathogenic in a multifactorial analysis based in part to segregation and tumor pathology likelihood ratios of 18.9 and 1134.1, respectively (PMID: 31131967). This variant has been identified in 1/249776 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. -
Jul 14, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
Dec 14, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jun 28, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
RNA studies demonstrate a damaging effect: results in aberrant splicing leading to a 65bp insertion and predicted null allele (PMID: 16619214); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 30209399); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as 5105+6 T>G and IVS16+6 T>G; This variant is associated with the following publications: (PMID: 11179017, 22160602, 24667779, 21324516, 21913181, 23348723, 31131967, 32719484, 30426508, 34645131, 31360904, 16619214, 30209399) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes a T>G nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. This variant is also known as 5105+6T>G and IVS16+6T>G in the literature. RNA studies on carrier-derived RNA (PMID: 16619214) and in a mini-gene splicing assay (PMID: 24667779) have found this variant to disrupt splicing in a manner that is expected to result in an absent or non-functional protein product. This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals with personal and/or family history of breast and ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). This variant also has been reported as pathogenic in a multifactorial analysis based in part to segregation and tumor pathology likelihood ratios of 18.9 and 1134.1, respectively (PMID: 31131967). This variant has been identified in 1/249776 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. -
Oct 10, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4986+6T>G intronic pathogenic mutation variant results from a T to G substitution 6 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Schubert S et al. Int. J. Cancer 2019 Jun;144(11):2683-2694; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). RNA splicing analyses have shown this alteration to result in aberrant splicing that results in the insertion of 65 nucleotides and results in nonsense-mediated mRNA decay (Ambry internal data; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature 2018 10;562(7726):217-222). In addition, this alteration was also classified as Pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 Sep;40(9):1557-1578). Of note, this alteration is also referred to as 5105+6T>G and IVS16+6T>G in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80358086, gnomAD 0.0009%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11179017, 16619214, 21913181, 22160602). ClinVar contains an entry for this variant (Variation ID: 55344). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16619214, 24667779, 30209399; internal data). This variant disrupts the c.4986+6T nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10406662, 21120943, 21324516, 21965345, 24729269). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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
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Breast and/or ovarian cancer Pathogenic:1
Mar 08, 2017
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Malignant tumor of breast Pathogenic:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
The c.4986+6T>G variant has been previously reported in the literature in 1 out of 1298 proband chromosomes, in an individual with ovarian cancer (Risch 2001). The variant has also been identified by our laboratory in one family where the variant was demonstrated to segregate with disease in 5 affected family members with breast cancer, suggesting this variant is pathogenic. In the UMD, BIC and LOVD databases, an intronic mutation at the same genomic location but with a different base alteration (IVS16+16 T>C) was described as being a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site. It is listed in the dbSNP database (rs80358086) but no frequency information was provided and so the population frequency could not be assessed. The variant is located in the 5' splice region but does not affect the highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In summary, based on above information, this variant is classified as pathogenic. -
Breast carcinoma Pathogenic:1
Aug 08, 2021
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences