Submissions for variant NM_007294.4(BRCA1):c.213-11T>G

gnomAD frequency: 0.00001  dbSNP: rs80358061

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047725	SCV000075738	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	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 present in population databases (rs80358061, gnomAD 0.003%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7894493, 10923033, 18284688, 21993507, 22144684, 25452441). It has also been observed to segregate with disease in related individuals. This variant is also known as c.332-11T>G and IVS5-11T>G. ClinVar contains an entry for this variant (Variation ID: 37449). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18424508, 23451180; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074570	SCV000108655	pathogenic	not provided	2017-09-12	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.213-11T>G or IVS4-11T>G and consists of a T>G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 332-11T>G or BRCA1 IVS5-11T>G using alternate nomenclature. RNA and minigene assays have demonstrated that BRCA1 c.213-11T>G causes aberrant splicing through activation of a cryptic splice acceptor site, introducing a premature stop codon and leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Bonnet 2008, Colombo 2013). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer, and has been shown to segregate with disease (Friedman 1994, Musolino 2005, John 2007, Colombo 2013, Song 2014, Wong-Brown 2015). We consider this variant to be pathogenic.
Ambry Genetics	RCV000131898	SCV000186953	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The c.213-11T>G intronic pathogenic mutation results from a T to G substitution eleven nucleotides before coding exon 4 of the BRCA1 gene. In three in vitro studies, this mutation was found to activate a cryptic splice site that leads to the retention of 59 base pairs at the 5' end of coding exon 4, leading to a premature stop codon and a truncated protein product (Colombo M et al. PLoS One. 2013 Mar;8:e57173; Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). In addition, this mutation has been observed in multiple breast and ovarian cancer families to date (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Hall MJ et al. Cancer. 2009 May;115:2222-33; John EM et al. JAMA. 2007 Dec;298:2869-76; Musolino A et al. Tumori. 2005 Nov-Dec;91:505-12), including one in which this mutation was reported to segregate with disease through three generations (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404). Of note, this mutation is also designated as IVS5-11T>G and 75Stop in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000031030	SCV000220836	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-24	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000131898	SCV000292144	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -11 position of intron 4 of the BRCA1 gene. RNA studies have shown that this variant causes retention of 59 nucleotides at the 3' end of intron 4 (PMID: 18424508, 23451180). This is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. This variant has been reported to segregate with disease in a large family affected with breast and ovarian cancer (PMID: 7894493), and has been observed in several unrelated individuals affected with breast, ovarian and/or endometrial cancer (PMID: 18284688, 21993507, 25452441, 10923033, 22144684, 33484353, 34072659). This variant has also been identified in 3/250918 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074570	SCV000296273	pathogenic	not provided	2019-05-10	criteria provided, single submitter	clinical testing	This variant has been reported in hereditary breast/ovarian cancer families in the published literature (PMIDs: 7894493 (1994), 16457150 (2005), 18159056 (2007), 21170264 (2010), 21993507 (2012), 23451180 (2013), 24728189 (2014), 25682074 (2015), and 27062684 (2016)). RNA splicing studies have shown that this variant interferes with BRCA1 mRNA splicing by activating a cryptic splice-site and causing the inclusion of 59 base pairs of intronic sequence in the BRCA1 mRNA (PMIDs: 18424508 (2008), 22505045 (2012), and 23451180 (2013). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031030	SCV000325254	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469831	SCV000540930	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074570	SCV000602679	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The BRCA1 c.213-11T>G variant, also known as 332-11T>G or IVS5-11T>G, is reported in the medical literature in multiple individuals and families with breast and/or ovarian cancer (Carter 2018, Friedman 1994, Yost 2019). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37449). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, in silico analyses and experimental evidence demonstrate this variant causes aberrant intronic splicing (Bonnet 2008, Colombo 2013). Based on available information, this variant is classified as pathogenic. References: Bonnet C et al. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet. 2008 Jul;45(7):438-46. PMID: 18424508. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Colombo M et al. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One. 2013;8(2):e57173. PMID: 23451180. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. Yost S et al. Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers. JNCI Cancer Spectr. 2019 Apr 19;3(2):pkz028. PMID: 31360904.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047725	SCV000698919	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.213-11T>G variant affects a conserved intronic nucleotide. 3/5 splice-site tools predict the variant to create a new cryptic splice site and/or weaken the cononical splice site. This in silico predicted result is proven by multiple functional studies showing that this variant leads to a splicing defect, resulting in an extra 59 base pairs at the end of intron 4 and introducing a premature stop codon. This variant was found in 1/121156 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). However, the variant has been found in multiple HBOC patients or individuals undergoing BRCA1/2 testing as reported in literature and clinical databases. Additionally, several clinical labs and clinical databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047725	SCV000966958	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-20	criteria provided, single submitter	clinical testing	The c.213-11T>G variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and has segregated with disease in multiple affected relati ves (Friedman 1994, John 2007, Smith 2012, Wong-Brown 2015, BIC database). This variant has also been reported by multiple clinical laboratories in ClinVar (Var iation ID# 37449). Additionally, this variant has been identified in 3/111540 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org). Sequencing of patient RNA has shown that this variant leads to a retention of 59 base pairs at the 3' end of intron 5, which is predicted to r esult in a premature stop codon (Friedman 1994, Colombo 2013). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individual s with hereditary breast and/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the frequency in patients and segregation studies. ACMG/AMP cr iteria applied: PS4, PP1_Strong.
Revvity Omics, Revvity	RCV000074570	SCV003810368	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031030	SCV004212694	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-22	criteria provided, single submitter	clinical testing
OMIM	RCV000031030	SCV000039520	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031030	SCV000053624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031030	SCV000144670	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047725	SCV000587038	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735531	SCV000863669	pathogenic	Breast and/or ovarian cancer	2007-01-26	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000047725	SCV002760023	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-14-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.