Submissions for variant NM_007294.4(BRCA1):c.4243del (p.Glu1415fs)

gnomAD frequency: 0.00001  dbSNP: rs80357981

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031159	SCV000300095	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	RCV000217565	SCV000274996	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	clinical testing	The c.4243delG pathogenic mutation, located in coding exon 11 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4243, causing a translational frameshift with a predicted alternate stop codon (p.E1415Kfs*4). This pathogenic mutation has been reported in several unrelated breast and/or ovarian cancer families (Smith LD et al. Breast Cancer Res. 2011 Jan 31;13(1):R14; Konecny M et al. Breast Cancer Res Treat. 2011 Feb;126(1):119-30; Machackova E et al. Klin Onkol. 2019;32:51-71). Of note, this alteration is also designated as 4362delG 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031159	SCV000325906	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482127	SCV000566521	pathogenic	not provided	2022-11-23	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; Published functional studies demonstrate a damaging effect: significant reduction in HDR activity compared to wild-type (Lu C et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4362del; This variant is associated with the following publications: (PMID: 29625052, 21203900, 21281505, 26689913, 24312913, 16267036, 28452373, 29452958, 30720243, 29922827)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000482127	SCV000883469	pathogenic	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482127	SCV000888913	pathogenic	not provided	2018-03-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217565	SCV001345619	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 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 one individual affected with breast cancer (PMID: 21281505) and in several suspected hereditary breast and ovarian cancer families (PMID: 21203900, 29446198, 31409081). This variant has been identified in 1/251428 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	RCV000496518	SCV001362810	pathogenic	Hereditary breast ovarian cancer syndrome	2019-07-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4243delG (p.Glu1415LysfsX4) 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 allele was found at a frequency of 4e-06 in 251428 control chromosomes (gnomAD). c.4243delG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Smith_2011, Konecny_2011, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of HDR activity (Lu_2015). Six ClinVar submissions 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000482127	SCV001449883	pathogenic	not provided	2017-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496518	SCV001579487	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 21203900, 21281505). This variant is present in population databases (rs80357981, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu1415Lysfs*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 also known as c.4362delG. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37578).
Baylor Genetics	RCV000031159	SCV005058251	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031159	SCV000053759	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031159	SCV000145038	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-07-22	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496518	SCV000587384	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354027	SCV000591499	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1415LysfsX4 variant was identified in 4 of 2104 proband chromosomes (frequency: 0.002) from individuals or families with Hereditary Breast and ovarian Cancer (Konecny 2011, Smith 2011). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 67690 chromosomes (frequency: 1.48e-05) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The variant was also identified in dbSNP (ID: rs80357981) “With Pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, as pathogenic by BIC ), GeneInsight VariantWire(1X, classified as pathogenic by a clinical laboratory), the BIC database (2X with clinical importance). The p.Glu1415LysfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1415 and leads to a premature stop codon 4 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.
CZECANCA consortium	RCV001271022	SCV001451836	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing