ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.815_824dup (p.Thr276fs)

dbSNP: rs387906563
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000019258 SCV000323916 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000049156 SCV000077169 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr276Alafs*14) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs387906563, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 9150149, 10417303, 26681312, 28503720). This variant is also known as 926ins10, ter289, and 943ins10. ClinVar contains an entry for this variant (Variation ID: 55723). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074602 SCV000108688 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and has been described as a pathogenic founder variant of African origin (Mefford 1999, Pal 2004, Stoppa-Lyonnet 1997, Walsh 2011, Villarreal-Garza 2015, Rummel 2017); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 926ins10, 934_943dup10, or 943ins10; This variant is associated with the following publications: (PMID: 26071757, 32025337, 27742776, 22006311, 9150149, 15533909, 10417303, 25920394, 26681312, 25256238, 22739995, 28944232, 28503720, 30262796, 30720243, 30322717, 31331294, 25716084, 31447099, 32832836, 32341426, 33646313)
Ambry Genetics RCV000129599 SCV000184383 pathogenic Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing The c.815_824dup10 pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of AGCCATGTGG at nucleotide position 815, causing a translational frameshift with a predicted alternate stop codon (p.T276Afs*14). This pathogenic mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) syndrome families, and it has been established as a founder mutation of African origin (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Mefford HC et al. Am. J. Hum. Genet. 1999 Aug;65:575-8; Panguluri RC et al. Hum. Genet. 1999 Jul-Aug;105:28-31; Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13:1794-9; Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Zhang J et al. Breast Cancer Res. Treat. 2012 Jul;134:889-94; Jara L et al. Biol. Res. 2017 Oct;50:35). Of note, this alteration is also designated as 943ins10 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074602 SCV000296290 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282168 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33646313 (2021), 32341426 (2020), 31331294 (2019), 30262796 (2018)) and ovarian cancer (PMID: 30322717 (2018)). In addition, this variant has been reported as a founder mutation of African origin (PMID: 10417303 (1999), 21120943 (2011), 22762150 (2012)). 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 RCV000019258 SCV000326435 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000468976 SCV000540938 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genologica Medica RCV000019258 SCV000577918 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000019258 SCV000677715 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-03-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129599 SCV000683367 pathogenic Hereditary cancer-predisposing syndrome 2023-10-01 criteria provided, single submitter clinical testing This variant inserts 10 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least fifteen individuals and over two dozen families affected with breast and ovarian cancer (PMID: 9150149, 10417303, 15533909, 19241424, 20838878, 21120943, 22006311, 21913181, 22739995, 26681312, 28503720, 28944232, 30322717, 32025337, 32341426, 33646313, 34413315) and prostate cancer (PMID: 32832836). Haplotype analysis suggests that this variant may be founder mutation originating from West African (PMID: 10417303, 32025337). This variant has been identified in 2/282168 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049156 SCV000699312 pathogenic Hereditary breast ovarian cancer syndrome 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.815_824dupAGCCATGTGG (p.Thr276Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.843_846delCTCA/p.Ser282fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121190 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000019258 SCV000839904 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-08-21 criteria provided, single submitter clinical testing The c.815_824 frameshift change in BRCA1 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 9150149, 10417303, 22006311, 15533909]. This variant is classified as pathogenic. It is recommended that the zygosity (heterozygous vs. mosaic) of this change be confirmed by Sanger sequencing as NGS variant calling may lead to skewed allele fractions for an indel of this size.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000074602 SCV002506134 pathogenic not provided 2022-01-13 criteria provided, single submitter clinical testing The BRCA1 c.815_824dup; p.Thr276AlafsTer14 variant (rs387906563) is reported in multiple individuals affected with breast and ovarian cancer (Mefford 1999, Stoppa-Lyonnet 1997, Walsh 2011, Zayas-Villanueva 2019). This variant is also reported in ClinVar (Variation ID: 55723), and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting 10 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Mefford HC et al. Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet. 1999 Aug;65(2):575-8. PMID: 10417303. Stoppa-Lyonnet D et al. BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet. 1997 May;60(5):1021-30. PMID: 9150149. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311. Zayas-Villanueva OA et al. Analysis of the pathogenic variants of BRCA1 and BRCA2 using next-generation sequencing in women with familial breast cancer: a case-control study. BMC Cancer. 2019 Jul 22;19(1):722. PMID: 31331294.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000019258 SCV002512517 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-10-06 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Sema4, Sema4 RCV000129599 SCV002537923 pathogenic Hereditary cancer-predisposing syndrome 2021-03-29 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002496721 SCV002809679 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2021-12-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000074602 SCV004041998 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing BRCA1: PVS1, PM2
Baylor Genetics RCV000019258 SCV004212738 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000074602 SCV004224916 pathogenic not provided 2022-08-05 criteria provided, single submitter clinical testing PP5, PM2, PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000049156 SCV004847396 pathogenic Hereditary breast ovarian cancer syndrome 2023-12-13 criteria provided, single submitter clinical testing The p.Thr276AlafsX14 variant in BRCA1 has been reported in multiple individuals with BRCA1-associated cancers bnand is believed to be a founder variant of African origin (Stoppa-Lyonnet 1997 PMID: 9150149, Mefford 1999 PMID: 10417303, Walsh 2011 PMID: 22006311, Buleje 2017 PMID: 28944232). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 55723) and has been identified in 0.01% (4/41360) of African or African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 276 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In the compound heterozygous or homozygous state, these variants are associated with autosomal recessive Fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting.
OMIM RCV000019258 SCV000039546 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1999-08-01 no assertion criteria provided literature only
Centro de Genética y Biología Molecular, Universidad de San Martín de Porres RCV000019258 SCV000263346 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-03-09 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735513 SCV000863651 pathogenic Breast and/or ovarian cancer 2014-12-18 no assertion criteria provided clinical testing
GeneReviews RCV000049156 SCV002097627 not provided Hereditary breast ovarian cancer syndrome no assertion provided literature only Founder variant in those of West African ancestry
BRCAlab, Lund University RCV000019258 SCV004244145 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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