Submissions for variant NM_007294.4(BRCA1):c.3288_3289del (p.Leu1098fs)

dbSNP: rs80357686

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112048	SCV000299910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112048	SCV000325600	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509738	SCV000608081	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-25	criteria provided, single submitter	clinical testing	The c.3288_3289delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3288 to 3289, causing a translational frameshift with a predicted alternate stop codon (p.L1098Sfs*4). This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Peyrat JP et al. Eur. J. Cancer Prev. 1998 Feb;7 Suppl 1:S7-12; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Wen WX et al. J Med Genet, 2018 02;55:97-103; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 3407delAA 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.
GeneKor MSA	RCV000585665	SCV000693525	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a deletion of two nucleotides, resulting in a frameshift and the creation of a novel stop codon after 4 amino acid residues. It is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA1 gene are known to be pathogenic. The mutation is also known as BRCA1 3407delAA. The mutation database Clinvar contains entries for this variant (Variation ID: 54821).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496891	SCV000699014	pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3288_3289delAA (p.Leu1098Serfs) 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. If a protein product is made, it is predicted to truncate the highly conserved BRCT domain. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3296delC/p.Pro1099fs). One in silico tool predicts a damaging outcome for this variant. This variant was absent in 121236 control chromosomes, but has been reported in multiple HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585665	SCV000887663	pathogenic	not provided	2018-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509738	SCV001348547	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This variant deletes 2 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 five individuals affected with breast cancer and/or ovarian cancer (PMID: 10866029, 15063971, 21324516, 26187060, 30287823). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496891	SCV001589619	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1098Serfs*4) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is also known as 3407delAA. ClinVar contains an entry for this variant (Variation ID: 54821). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000112048	SCV004215176	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-31	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112048	SCV000144701	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	RCV000496891	SCV000587294	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000112048	SCV005061286	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control