Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.4097-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6, offset of 1, new splice context is: tctgtttttgttatttaaAGtga. 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;
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 17-43091033-C-T is Pathogenic according to our data. Variant chr17-43091033-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37567.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091033-C-T is described in Lovd as [Pathogenic]. Variant chr17-43091033-C-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Dec 23, 2008
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Nov 25, 2004
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Aug 10, 2015
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 = 1 -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
May 22, 2022
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
research
Genetics Program, Instituto Nacional de Cancer
Nov 01, 2021
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Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Aug 11, 2019
This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). 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. Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). This variant has been observed in individuals referred for genetic testing (PMID: 17924331). This variant is also known as IVS11-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37567). This sequence change affects an acceptor splice site in intron 10 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 30, 2020
The c.4097-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of 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). This nucleotide position is highly conserved in available vertebrate species. In addition, the BDGP and ESEfinder in silico splicing models predict the creation of a new alternate splice donor site. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 likely pathogenic. -