Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_007294.4(BRCA1):c.5333-6T>G variant causes a splice region, 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43049200-A-C is Pathogenic according to our data. Variant chr17-43049200-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55538.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, not_provided=2, Likely_pathogenic=5}.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-1.01). . Strength limited to SUPPORTING due to the PP5.
Likely pathogenic, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jun 01, 2021
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Likely pathogenic, criteria provided, single submitter
clinical testing
Mayo Clinic Laboratories, Mayo Clinic
Jun 13, 2024
PP4, PM2, PS3 -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Feb 28, 2024
The BRCA1 c.5333-6T>G variant has been reported in the published literature in an individual with a personal and/or family history of breast and ovarian cancer (PMID: 11802209 (2002)). It was also reported to result in exon 22 skipping (PMID: 31131967 (2019)), as well as being non-functional using a saturation genome editing assay (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing (Alamut Visual (http://www.interactive-biosoftware.com/). Based on the available information, we are unable to determine the clinical significance of this variant. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Dec 01, 2022
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Likely pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 08, 2024
This variant causes a T to G nucleotide substitution at the -6 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant causes the out-of-frame skipping of exon 21 (PMID: 11802209) and this variant also has been reported in ClinVar to cause abnormal splicing (SCV002646843.1). A functional assay that required proper splicing for the measured activity has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). Since this variant does not directly impact the coding sequence, the splicing prediction, RNA data and functional data could be interpreted together as evidence for a significant disruption in RNA processing. This variant has been detected in an individual affected with breast cancer and reported in two families affected with breast cancer and both breast and ovarian cancer (PMID: 11802209; Color internal data). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation and tumor pathology of 0.6846 and 3.73, respectively (PMID: 31131967). 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 Likely Pathogenic. -
The c.5333-6T>G intronic pathogenic mutation results from a T to G substitution 6 nucleotides upstream from coding exon 20 in the BRCA1 gene. This nucleotide position is well conserved in available vertebrate species. This alteration was detected in 1/989 unrelated individuals from a cohort of German breast and/or ovarian cancer families (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). One study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, was called likely pathogenic based on multifactorial likelihood analysis (Parsons MT et al. Hum. Mutat. 2019 09;40:1557-1578). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 16, 2023
This variant causes a T to G nucleotide substitution at the -6 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant causes the out-of-frame skipping of exon 21 (PMID: 11802209) and this variant also has been reported in ClinVar to cause abnormal splicing (SCV002646843.1). A functional assay that required proper splicing for the measured activity has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). Since this variant does not directly impact the coding sequence, the splicing prediction, RNA data and functional data could be interpreted together as evidence for a significant disruption in RNA processing. This variant has been detected in an individual affected with breast cancer and reported in two families affected with breast cancer and both breast and ovarian cancer (PMID: 11802209; Color internal data). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation and tumor pathology of 0.6846 and 3.73, respectively (PMID: 31131967). 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 Likely Pathogenic. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
May 01, 2021
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399). This variant has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 11802209). This variant is also referred to as IVS21-6T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55538). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 20 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. -
Familial cancer of breast Other:1
not provided, no classification provided
literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)