17-43104968-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.213-12A>G variant causes a 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. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA1
NM_007294.4 intron
NM_007294.4 intron
Scores
2
Splicing: ADA: 0.9981
2
Clinical Significance
Conservation
PhyloP100: 0.312
Genes affected
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43104968-T-C is Pathogenic according to our data. Variant chr17-43104968-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 37450.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104968-T-C is described in Lovd as [Likely_pathogenic]. Variant chr17-43104968-T-C is described in Lovd as [Pathogenic]. Variant chr17-43104968-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.213-12A>G | intron_variant | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.213-12A>G | intron_variant | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 30, 1999 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | 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, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 09, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 06, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 08, 2022 | - - |
not provided Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 27, 2023 | PP5, PM2, PS3, PS4_moderate - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 c.213-12A>G variant was identified in 6 of 11748 proband chromosomes (frequency: 0.0005) from Spanish, Korean, German, Austrian, Malayasian and Dutch individuals or families with high risk breast and ovarian cancer, or triple negative breast cancer (de Juan Jimenez_2013_23479189, Kang_2015_25863477, Meindl_2002_11802209, Muendlein_2015_25971625, Thirthagiri_2008_18627636, van der Hout_2006_16683254). One case report describes a patient diagnosed with endometrial cancer at 46 and a triple negative breast cancer at 33 as carrying two pathogenic mutations BRCA1 c.213-12A>G, p.Arg71SerfsX21 and MSH6 c.515_516insT, p.Ile172fsX10 (Kast_2012_ 23164213). The c.213-12A>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant was initially identified in a family with a history of breast cancer, segregating with the disease, and RT-PCR analysis on whole blood lymphocyte showed an 11 nucleotide insert at the intron 4/exon 6 boundary leading to a frameshift and truncated protein (Hoffman_1998_ 9805131). The variant was also identified in dbSNP (ID: rs80358163) “With Pathogenic allele”, ClinVar (classified pathogenic (last evaluated 2017); submitters: pathogenic by Ambry Genetics, GeneDx, Michigan Medical Genetics Laboratories (University of Michigan), Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), Quest Diagnostics Nichols Institute San Juan Capistrano, CIMBA, Counsyl, Invitae, SCRP, BIC ), Clinvitae (4x), GeneInsight-COGR (as pathogenic by 3 clinical laboratories ), BIC Database (25x with clinical importance, classification pending), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database (1x) and was not identified in Cosmic, MutDB, LOVD 3.0, UMD-LSDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 13, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2024 | Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 9805131, 21735045); Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (PMID: 9805131, 11802209, 18627636, 15024741, 23479189, 25863477); Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial likelihood analysis suggests this variant is pathogenic (PMID: 31131967); Also known as 332-12A>G or IVS5-12A>G; This variant is associated with the following publications: (PMID: 15024741, 29053726, 21394499, 27836010, 28528518, 31492746, 11802209, 18627636, 23479189, 9805131, 24285858, 23164213, 25863477, 26681312, 26659639, 27221827, 28324225, 29360161, 28993434, 30702160, 30093976, 30875412, 31825140, 21735045, 31131967, 25971625, 24667779, 37239058, 29446198, 21147080, 21348412) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 20, 2020 | In the published literature, this variant has been reported in multiple families affected with hereditary breast and/or ovarian cancer as well as individuals affected with pancreatic and endometrial cancers (PMIDs: 9805131 (1998), 11802209 (2002), 16683254 (2006), 18627636 (2008), 23164213 (2012), 23479189 (2013), 25863477 (2015), 25971625 (2015), 28528518 (2017), and 29360161 (2018)). In addition, this variant is described in the published literature as interfering with normal splicing of the BRCA1 mRNA by activating a cryptic splice site and causing the inclusion of 11 base pairs of intronic sequence in the BRCA1 mRNA. The inclusion of this intronic sequence alters the translation reading frame of the BRCA1 mRNA and is predicted to cause the synthesis of a truncated BRCA1 protein (PMID: 23164213 (2012), 21735045 (2012), and 9805131 (1998)). - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 19, 2016 | The c.213-12A>G variant in BRCA1 has been reported in >25 individuals with BRCA1 -associated cancers and segregated with disease in 4 affected relatives from 2 f amilies (Dong 1998, Hoffman 1998, Meindl 2002, Thirthagiri 2008, Kast 2012, de J uan Jimenez 2013, Brohet 2014,Breast Cancer Information Core (BIC) database). Th is variant was absent from large population studies. In vitro functional studies provide evidence that the c.213-12A>G variant introduces a cryptic splice site, causing an additional 11 nucleotides to be retained and leading to a frameshift , which alters the protein?s amino acid sequence beginning at position 71 and le ads to a premature termination codon 21 amino acids downstream (Hoffman 1998, Me nendez 2012). This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established dise ase mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this v ariant meets our criteria to be classified as pathogenic for HBOC in an autosoma l dominant manner based upon segregation studies, absence from controls, and fun ctional evidence. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2022 | Variant summary: BRCA1 c.213-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' splice acceptor site. Two predict the variant creates a new 3' acceptor site at position -12. At least one publication reports experimental evidence that this variant affects mRNA splicing by incorporation of 11 bases of intron 5 leading to a frameshift in the codon sequence (Hoffman_1998). The variant was absent in 250918 control chromosomes. c.213-12A>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change falls in intron 4 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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9805131, 19563646, 21348412, 23479189). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS5-12A>G. ClinVar contains an entry for this variant (Variation ID: 37450). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 9805131; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2022 | The c.213-12A>G intronic pathogenic mutation results from an A to G substitution 12 nucleotides upstream from coding exon 4 in the BRCA1 gene. This alteration has been reported in numerous individuals with personal and/or family history of breast and/or ovarian cancers (Meindl A et al. Int. J. Cancer, 2002 Feb;97:472-80; Thirthagiri E et al. Breast Cancer Res., 2008 Jul;10:R59; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Brohet RM et al. J. Med. Genet., 2014 Feb;51:98-107; Kang E et al. Breast Cancer Res. Treat., 2015 May;151:157-68; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Cock-Rada AM et al. Fam. Cancer. 2018 Jan;17:23-30; Wen WX et al. J. Med. Genet., 2018 Feb;55:97-103; Dudley B et al. Cancer, 2018 Apr;124:1691-1700). In one 11-person family with early-onset breast cancer this mutation was shown to segregate with disease (Hoffman JD et al. Am. J. Med. Genet. 1998 Nov;80(2):140-4). This alteration results in the formation of a cryptic splice acceptor site, leading to an insertion of 11 nucleotides with a predicted premature termination codon (Ambry internal data; Hoffman JD et al. Am. J. Med. Genet. 1998 Nov;80(2):140-4; Menedez M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):979-92). Of note, this mutation is also designated as IVS5-12A>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 10, 2023 | This variant causes an A to G nucleotide substitution at the -12 position of intron 4 of the BRCA1 gene. An RNA study has shown that this variant causes new splice acceptor that inserts 11 bp at the beginning of exon 6, resulting in frameshift and premature truncation within exon 6 (PMID: 9805131). This variant has been reported in at least six individuals and multiple families affected with breast or ovarian cancer (PMID: 9760198, 9805131, 18627636, 21147080, 25863477, 25971625, 28528518), and in an individual affected with pancreatic and ovarian cancer (PMID: 29360161). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation and tumor pathology of 29429 and 1132, 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 Pathogenic. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 10, 2017 | - - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2024 | The BRCA1 c.213-12A>G variant is predicted to interfere with splicing. This variant has been reported several times in patients and families with hereditary breast and ovarian cancer syndrome (HBOC) (Hoffman et al., 1998. PubMed ID: 9805131; de Juan Jiménez et al., 2013. PubMed ID: 23479189; Rebbeck et al., 2016. PubMed ID: 27836010; Susswein et al., 2016. PubMed ID: 26681312). The c.213-12A>G variant has been shown by RT-PCR to alter normal splicing of intron 5 (Hoffman et al., 1998. PubMed ID: 9805131; Menéndez et al., 2012. PubMed ID: 21735045). This variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37450/). Therefore, this variant is interpreted as pathogenic. - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -1
DS_AL_spliceai
Position offset: -12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at