Submissions for variant NM_007294.4(BRCA1):c.1961del (p.Lys654fs)

dbSNP: rs80357522

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031019	SCV000282269	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000047660	SCV000075673	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys654Serfs*47) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast, ovarian, and endometrial cancer (PMID: 7493024, 12955716, 17645508, 23633455, 26026974). This variant is also known as 2073delA and 2080delA. ClinVar contains an entry for this variant (Variation ID: 37438). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130764	SCV000185656	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	clinical testing	The c.1961delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.K654Sfs*47). This mutation has been reported numerous times in the literature in breast and breast/ovarian cancer families, including in a case of male breast cancer (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; George J et al. Clin. Cancer Res. 2013 Jul;19(13):3474-84; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12(4):767-77; Abugattas J et al. Clin. Genet. 2015 Oct;88(4):371-5; de Juan I et al. Fam. Cancer, 2015 Dec;14:505-13; Meisel C et al. Arch Gynecol Obstet. 2017 May;295(5):1227-1238). Of note, this alteration is also designated as 2080delA 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031019	SCV000195897	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000236783	SCV000292510	pathogenic	not provided	2020-11-10	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 a personal or family history consistent with pathogenic variants in this gene, and reported as a recurrent variant in Spanish populations (Gayther 1995, Risch 2001, Diez 2003, de Juan Jimenez 2013, Abugattas 2015, Couch 2015, de Juan 2015, Kang 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25452441, 11595708, 27376475, 16455195, 11956590, 26026974, 29310832, 7493024, 23633455, 12955716, 22798144, 11179017, 20727672, 17645508, 14517958, 16234499, 25256238, 25863477, 23479189, 26295337, 27533253, 27167707, 28324225, 29928469, 28831036, 29907814, 30606148, 30720863, 28176296, 30720243, 30014164, 30322717, 31090900, 29625052, 26689913, 30350268, 31214711, 33654310, 32341426, 31825140)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236783	SCV000296329	pathogenic	not provided	2020-05-27	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000047660	SCV000324814	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-03	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031019	SCV000325202	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000047660	SCV000403071	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing	The c.1961delA (p.Lys654SerfsTer47) variant (also commonly referred to as c.2080delA) results in a frameshift, and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys654SerfsTer47 variant has been identified in a heterozygous state in 29 cases of breast or ovarian cancer (Gayther et al. 1995; Risch et al. 2001; Curci et al. 2002; Diez et al. 2003; Martinez-Ferrandis et al. 2003; Ahn et al. 2007; Kwon et al. 2008; Iyevleva et al. 2010; Kim et al. 2012; Kang et al. 2015; de Juan Jiminez et al. 2013; George et al. 2013; Abugattas et al. 2014; Silva et al. 2014). The variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (Non-Finnish) population of the Exome Aggregation Consortium Project but this is based on one allele so the variant is presumed to be rare. Most variants in the BRCA1 gene that have been shown to be associated with breast and ovarian cancer are frameshift variants resulting in a non-functional protein. Based on the potential impact of frameshift variants and the available evidence, the p.Lys654SerfsTer47 variant is classified as pathogenic for hereditary breast and ovarian cancer syndrome.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414241	SCV000492455	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Genologica Medica	RCV000031019	SCV000577925	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000047660	SCV000588035	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130764	SCV000688356	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2073delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over 20 individuals and families affected with breast, ovarian and endometrial cancer (PMID: 7493024, 11179017, 11956590, 14517958, 14760071, 16455195, 17645508, 20727672, 22711857, 22798144, 23479189, 25256238, 28324225, 33471991; Leiden Open Variation Database DB-ID BRCA1_000177) and one individual each affected with prostate cancer (PMID: 31214711) and hemangioblastoma (PMID: 24884479). This variant has been identified in 3/282102 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.
GeneKor MSA	RCV000047660	SCV000693514	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single base pair deletion at amino acid residue 654 of the BRCA1 gene. It results in a frame-shift, creating a new stop codon after 47 amino acids, thus resulting in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic. This variant is also known as 2073delA and 2080delA and has been reported in the literature in patients affected with breast, ovarian, and endometrial cancer (PMID: 7493024, 12955716, 17645508). The mutation database ClinVar contains entries for this variant (Variation ID: 37438).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047660	SCV000698901	pathogenic	Hereditary breast ovarian cancer syndrome	2020-07-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1961delA (p.Lys654SerfsX47) 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 8e-06 in 250730 control chromosomes (gnomAD). c.1961delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Gayther_1995, Grushko_2004, Alsop_2012, de Juan_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Sixteen ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic, while one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031019	SCV000744670	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031019	SCV000785270	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-27	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677808	SCV000803967	pathogenic	Infiltrating duct carcinoma of breast	2017-09-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000236783	SCV000806905	pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000031019	SCV001499619	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001705613	SCV001934342	pathogenic	Fanconi anemia, complementation group S	2020-11-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236783	SCV003809191	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236783	SCV004026796	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031019	SCV004212744	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031019	SCV000053612	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031019	SCV000144262	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031019	SCV000211994	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047660	SCV000587176	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353950	SCV000591357	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Lys654Serfs*47 variant was identified in 5 of 1160 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Al-Mulla 2008, de Juan 2015, Diez 2003). The variant was also identified in dbSNP (ID: rs80357522), ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and sixteen other submitters), and in LOVD 3.0 (58X ).The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1961del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 654 and leads to a premature stop codon at position 700. 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 BRCA1 associated cancers 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031019	SCV000733652	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000236783	SCV001906400	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000236783	SCV001932662	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250470	SCV002520892	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000031019	SCV004244108	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing