Submissions for variant NM_007294.4(BRCA1):c.3759_3760del (p.Lys1254fs)

dbSNP: rs80357520

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)	RCV000031125	SCV000300007	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.
GeneDx	RCV000254638	SCV000209884	pathogenic	not provided	2018-06-15	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in BRCA1 is denoted c.3759_3760delTA at the cDNA level and p.Lys1254GlufsX12 (K1254EfsX12) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGTC[delTA]AGAA. The deletion causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 1254, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.3759_3760delTA, also reported as 3878delTA using alternate nomenclature, has been published in association with breast and ovarian cancer in several individuals of Hispanic descent (John 2007, Villarreal-Garza 2015, Rebbeck 2016) and is considered pathogenic.
Ambry Genetics	RCV000223389	SCV000277585	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing	The c.3759_3760delTA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at positions 3759 and 3760, causing a translational frameshift with a predicted alternate stop codon (p.K1254Efs*12). This pathogenic mutation has been previously identified in multiple unrelated patients with breast cancer (John EM et al. JAMA. 2007 Dec;298:2869-76; Abugattas J et al. Clin. Genet. 2015 Oct;88:371-5; Villarreal-Garza C et al. Breast Cancer Res. Treat. 2015 Apr;150:389-94; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18(1):112). Of note, this alteration is also designated as 3878delTA in some published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000254638	SCV000296288	pathogenic	not provided	2019-10-01	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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported as pathogenic in individuals with breast cancer, especially in Hispanic populations (PMID: 30630528 (2019), 25628955 (2015), 18159056 (2007)). 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	RCV000031125	SCV000325744	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223389	SCV000683132	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-05	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 observed in at least 8 individuals affected with breast and ovarian cancer (PMID: 18159056, 25256238, 25716084, 30630528, 31753525; Color internal data). 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	RCV000587721	SCV000699070	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3759_3760delTA (p.Lys1254GlufsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251272 control chromosomes. c.3759_3760delTA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Finkelman_2012, John_2007, Judkins_2005, Llacuachaqui_2014, Millan_2019, Solano_2013, Villareal-Garza_2015 & 2021 etc.). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000587721	SCV001588430	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1254Glufs*12) 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 premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 18159056, 25236687, 25256238, 25628955, 27836010). This variant is also known as 3878delTA. ClinVar contains an entry for this variant (Variation ID: 37544). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482929	SCV002775624	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-12-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031125	SCV004215008	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031125	SCV000053724	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031125	SCV000144863	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing