Submissions for variant NM_007294.4(BRCA1):c.3279del (p.Tyr1094fs)

dbSNP: rs397509050

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112043	SCV000299905	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.
Ambry Genetics	RCV000165817	SCV000216564	pathogenic	Hereditary cancer-predisposing syndrome	2017-03-20	criteria provided, single submitter	clinical testing	The c.3279delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3279, causing a translational frameshift with a predicted alternate stop codon (p.Y1094Ifs*15). This mutation has been identified in one HBOC kindred of Dutch descent as well as in one HBOC kindred of Moroccan descent in which the proband and her mother were diagnosed with breast cancer at ages 32 and 49, respectively (van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66; Tazzite A et al. Gynecol. Oncol., 2012 Jun;125:687-92). In addition 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	RCV000112043	SCV000296428	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-17	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112043	SCV000325596	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482423	SCV000568416	pathogenic	not provided	2021-02-03	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 breast and/or ovarian cancer (Tazzite 2012, El Ansari 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 3398delC; This variant is associated with the following publications: (PMID: 23289006, 16683254, 25814778, 25885115, 23697973, 24606420, 22425665, 32778078, 30263132)
Invitae	RCV001387922	SCV001588679	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11897832, 16683254, 22425665). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54816). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1094Ilefs*15) 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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112043	SCV000144696	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499817	SCV000591434	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Tyr1094IlefsX15 deletion variant was identified in 2 of 942 proband chromosomes (frequency 0.002) from Moroccan or Dutch breast and/or ovarian cancer families (Tazzite 2012, van der Hout 2006). The variant was also identified in HGMD, UMD (4X as a causal variant), and once in the BIC database as a variant with clinical importance. The p.Tyr1094IlefsX15 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1094 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735519	SCV000863657	pathogenic	Breast and/or ovarian cancer	2013-08-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000482423	SCV001740845	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000482423	SCV001906243	pathogenic	not provided		no assertion criteria provided	clinical testing