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

dbSNP: rs387906563

Total submissions: 25

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.
Labcorp Genetics (formerly Invitae), Labcorp	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