Submissions for variant NM_007294.4(BRCA1):c.213-12A>G

dbSNP: rs80358163

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031031	SCV001161543	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167772	SCV000075739	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	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 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.
Ambry Genetics	RCV000131900	SCV000186955	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031031	SCV000195879	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000047726	SCV000210070	pathogenic	not provided	2024-05-03	criteria provided, single submitter	clinical testing	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167772	SCV000271314	pathogenic	Hereditary breast ovarian cancer syndrome	2016-01-19	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047726	SCV000296403	pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	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)).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031031	SCV000325255	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031031	SCV000487940	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505888	SCV000602725	pathogenic	not specified	2017-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131900	SCV000683015	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167772	SCV000698920	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-23	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000031031	SCV002764923	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-07-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504839	SCV002809861	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-09-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031031	SCV004215018	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000047726	SCV004224938	pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	PP5, PM2, PS3, PS4_moderate
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000047726	SCV005199758	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031031	SCV000053625	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031031	SCV000144671	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000167772	SCV000587039	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031031	SCV000733677	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758604	SCV000806910	pathogenic	BRCA1-related disorder	2024-07-08	no assertion criteria provided	clinical testing	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785201	SCV000923769	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
CZECANCA consortium	RCV001270969	SCV001451774	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000047726	SCV001548920	pathogenic	not provided		no assertion criteria provided	clinical testing	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000047726	SCV001797970	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000047726	SCV001951915	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000047726	SCV001968037	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031031	SCV002589067	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031031	SCV005061339	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control