Submissions for variant NM_007294.4(BRCA1):c.2214dup (p.Lys739Ter)

dbSNP: rs80357574

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241499	SCV000299723	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	RCV000166536	SCV000217337	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-08	criteria provided, single submitter	clinical testing	The c.2214dupT (p.K739*) alteration, located in exon 10 (coding exon 9) of the BRCA1 gene, consists of a duplication of T at position 2214, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in hereditary breast and/ovarian cancer cohorts (Mannan, 2016; Singh, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241499	SCV000325296	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000479756	SCV000571756	pathogenic	not provided	2025-02-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2333dup and c.2214_2215insT; This variant is associated with the following publications: (PMID: 26911350, 16267036, 27914478, 27848044, 30555256, 29470806, 35698740, 34601666, 20104584, 29446198)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501434	SCV000591372	pathogenic	Hereditary breast ovarian cancer syndrome	2015-03-30	criteria provided, single submitter	clinical testing
Molecular Diagnostics, Rajiv Gandhi Cancer Institute & Research Center	RCV000241499	SCV000678298	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-13	criteria provided, single submitter	clinical testing	Insertion of T introduces a new stop codon in exon 10 leading to a nonsense pathogenic alteration.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000501434	SCV000758889	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys739*) 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/or ovarian cancer (PMID: 26911350, 27914478). ClinVar contains an entry for this variant (Variation ID: 186881). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479756	SCV001133520	pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	The BRCA1 c.2214dup (p.Lys739*) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer and/or ovarian cancer (PMID: 16267036 (2005), 26911350 (2016), 30555256 (2018), 29470806 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501434	SCV001482174	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2214dupT (p.Lys739X) 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. The variant was absent in 250926 control chromosomes (gnomAD). c.2214dupT has been reported in the literature in individuals affected breast and Ovarian Cancer (example: Mehta_2018, Rebbeck_2018, Judkins_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000241499	SCV002761607	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-02-22	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000501434	SCV004046000	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in patients with breast and/or ovarian cancer (PMID: 26911350, 30555256). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.2214dup (p.Lys739Ter) variant is classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000241499	SCV004101484	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The observed frameshift c.2214dup(p.Lys739Ter) variant in BRCA1 gene has been reported previously in heterozygous state in individual(s) affected with breast and/or ovarian cancer (Mannan et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant is predicted to cause loss of normal protein function through protein truncation. This sequence change creates a premature translational stop signal (p.Lys739*) 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 (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000241499	SCV004215198	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000479756	SCV004242836	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166536	SCV004361025	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.2214_2215insT in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least 5 individuals affected with breast and/or ovarian cancer (PMID: 26911350, 30555256). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000501434	SCV004848519	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-22	criteria provided, single submitter	clinical testing	The p.Lys739X variant in BRCA1 has been reported in at least 5 individuals with BRCA1-associated cancers (Mannan 2016 PMID: 26911350, Maistro 2016 PMID: 27914478, Mehta 2018 PMID: 30555256, Singh 2018 PMID: 29470806). It was absent from large population studies. This variant is a duplication of one base (c.2214dupT) that results in a nonsense variant and leads to a premature termination codon at position 739, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Moreover, this variant was classified as pathogenic on September 8th, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 186881). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV005016505	SCV005647167	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-06-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005361017	SCV005915244	pathogenic	Fanconi anemia, complementation group S	2017-09-08	criteria provided, single submitter	clinical testing