Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5278-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000658 in 151,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.9, offset of 8, new splice context is: ctcttcttccacatcttcAGggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43051118-C-G is Pathogenic according to our data. Variant chr17-43051118-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 55501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43051118-C-G is described in Lovd as [Pathogenic]. Variant chr17-43051118-C-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4Other:1
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
- -
-
Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
- -
Dec 13, 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 G to C nucleotide substitution at the -1 position of intron 19 of the BRCA1 gene. A study using peripheral blood-derived RNA from a carrier has shown that this variant causes skipping of exon 20 (also known as exon 21 in the literature) and is expected to result in an absent or non-functional protein product (PMID: 22505045). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 12955716, 28802053, 29435039, 29752822, 30078507, 30287823, 30720863, 31528241, 35377489; Color internal data). 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. -
Aug 26, 2022
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Sep 30, 2010
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Hereditary breast ovarian cancer syndrome Pathogenic:3
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
- -
Jan 25, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5278-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Three predict the variant strengthens a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon skipping (Houdayer_2012). The variant was absent in 251146 control chromosomes (gnomAD. c.5278-1G>C has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, particularly individuals affected with breast cancer (e.g., de la Hoya_2002, Rashid_2006, Houdayer_2012, Lang_2017, Arai_2018, Deng_2019, Rashid_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that a haploid human cell line harboring the variant and in which BRCA1 was essential showed complete loss of fitness (Findlay_2018). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Sep 10, 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 19 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 11802208, 12955716, 16998791, 27553291, 28802053, 29176636). ClinVar contains an entry for this variant (Variation ID: 55501). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Sep 20, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Canonical splice site variant demonstrated to result in abnormal splicing leading to a null allele in a gene for which loss-of-function is a known mechanism of disease (Houdayer 2012); Observed in individuals with BRCA1-related cancer (de la Hoya 2002, Rashid 2016, Pelttari 2017, Fang 2018, Li 2019); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 5397-1G>C and IVS20-1G>C; This variant is associated with the following publications: (PMID: 11802208, 31131967, 22505045, 30209399, 29435039, 27553291, 29752822, 28802053, 12955716, 26681312, 30702160, 30720863, 30078507, 29446198, 25525159) -
Jun 28, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes a G to C nucleotide substitution at the -1 position of intron 19 of the BRCA1 gene. A study using peripheral blood-derived RNA from a carrier has shown that this variant causes skipping of exon 20 (also known as exon 21 in the literature) and is expected to result in an absent or non-functional protein product (PMID: 22505045). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 12955716, 28802053, 29435039, 29752822, 30078507, 30287823, 30720863, 31528241, 35377489; Color internal data). 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. -
Oct 07, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5278-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 19 of the BRCA1 gene. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families (De la Hoya M et al. Int J Cancer. 2002 Feb 1;97(4):466-71; Rashid MU et al. BMC Cancer. 2016 Aug 23;16(1):673; Pelttari LM et al. Clin Genet. 2017 Aug 12; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Fang M et al. Oncol Lett, 2018 Mar;15:3068-3074; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Li JY et al. Int J Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Deng M et al. Int J Cancer, 2019 09;145:1517-1528). RNA analyses demonstrated skipping of coding exon 19 (also known as exon 21) as a result of this alteration (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another functional 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). Of note, this alteration is also designated as IVS20-1G>C in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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. -