Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.81-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,012 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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009477826 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115780-C-T is Pathogenic according to our data. Variant chr17-43115780-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 91668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115780-C-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Other:1
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Aug 12, 2010
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
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Pathogenic, no assertion criteria provided
clinical testing
BRCAlab, Lund University
Mar 02, 2020
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Nov 16, 2023
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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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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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Dec 09, 2023
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; 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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 10644434, 22711857, 29446198); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 200-1G>A; This variant is associated with the following publications: (PMID: 25525159, 10644434, 29922827, 22711857, 29446198, 30078507, 30720243, 30787465, 36123164, 36243179, 30209399) -
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Dec 24, 2018
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 found in general population data that is consistent with pathogenicity. -
The c.81-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the BRCA1 gene. This mutation has been previously identified in multiple breast and/or ovarian cancer cohorts (Kroiss R et al. Hum Mutat. 2005 Dec;26(6):583-9; Alsop K et al. J Clin Oncol. 2012 Jul 20;30(21):2654-63). Of note, this alteration is also designated as IVS2-1G>A in published literature. 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
May 09, 2022
This variant causes a G to A nucleotide substitution at the -1 position of intron 2 splice acceptor site of the BRCA1 gene. This variant is also known as 200-1G>A and IVS2-1G>A in the literature. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A similar variant c.81-1G>C has been shown in RNA studies to impact the splicing of exon 3 that partially encodes the RING domain, which is important for BRCA1 function and is noted to have clinically relevant mutations (PMID: 22505045, 22737296, 23239986). This variant also has been reported to cause loss of BRCA1 function in haploid cell proliferation assays (PMID: 30209399, 31467430). This variant has been detected in at least three individuals and one family affected with ovarian cancer and breast cancer (PMID: 10644434, 22711857, 30287823). Three other similar variants at the -1 and -2 positions of this intron have been reported in at least 5 individuals affected with breast and ovarian cancer (PMID: 30078507, 32438681, 33461583, 33850850). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 18, 2022
Variant summary: BRCA1 c.81-1G>A 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. The variant allele was found at a frequency of 4e-06 in 250180 control chromosomes (gnomAD). c.81-1G>A has been reported in the literature in multiple individuals with personal and/or family history of breast and/or ovarian cancer (e.g. Momozawa_2018, Rebbeck_2018, Li_2018). These data indicate that the variant is very likely to be associated with disease. An in vitro study that assessed the effect of the variant in a haploid human cell line whose survival is dependent on intact BRCA1 function, and demonstrated a damaging effect for this variant (Findlay 2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 31, 2024
This sequence change affects an acceptor splice site in intron 2 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80358018, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 16287141, 22711857). ClinVar contains an entry for this variant (Variation ID: 91668). 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. -