Submissions for variant NM_007294.4(BRCA1):c.2679_2682del (p.Lys893fs)

dbSNP: rs80357596

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031062	SCV000282286	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047925	SCV000075938	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys893Asnfs*106) 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: 9145677, 22006311). This variant is also known as 2798delGAAA. ClinVar contains an entry for this variant (Variation ID: 37481). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131877	SCV000186932	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The c.2679_2682delGAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2679 to 2682, causing a translational frameshift with a predicted alternate stop codon (p.K893Nfs*106). This mutation has been detected in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Rummel S et al. Breast Cancer Res. Treat. 2013 Jan;137:119-25; Singer CF et al. Clin. Genet. 2014 Jan;85:72-5). Of note, this alteration is also designated as 2798del4 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.
Counsyl	RCV000031062	SCV000220601	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-08-19	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255129	SCV000296315	pathogenic	not provided	2020-12-18	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in multiple individuals and families affected with hereditary breast and/or ovarian cancer in the published literature (PMIDs: 8622478 (1996), 9145677 (1997), 16528604 (2006), 20104584 (2010), 22006311 (2011), 22333603 (2012), 22711857 (2012), 30972954 (2019), and 31090900 (2019)). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000255129	SCV000321421	pathogenic	not provided	2020-08-12	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; Identified in individuals with personal and family histories of breast and/or ovarian cancer (Couch 1997, Borg 2010, Walsh 2011, Alsop 2012, Deng 2019, Ashour 2019); 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 2798del4 or 2795del4; This variant is associated with the following publications: (PMID: 22006311, 9145677, 8622478, 26187060, 22711857, 20104584, 28497333, 30972954, 31372034, 27062684, 32341426, 31825140, 31090900)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031062	SCV000325426	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047925	SCV000605741	pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-28	criteria provided, single submitter	clinical testing	The p.Lys893fs variant in BRCA1 has been reported in >50 individuals with BRCA1- associated cancers (Couch 1997, Wagner 1998, Borg 2012, Walsh 2011, Lecarpentier 2012, Breast Cancer Information Core (BIC) database) and was absent from large population studies, though the ability of these studies to accurately detect ind els may be limited. This variant is predicted to cause a frameshift, which alter s the protein?s amino acid sequence beginning at position 893 and leads to a pre mature termination codon 106 amino acids downstream. Heterozygous loss of functi on of the BRCA1 gene is an established disease mechanism in individuals with her editary breast and ovarian cancer (HBOC). In summary, this variant meets our cri teria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Color Diagnostics, LLC DBA Color Health	RCV000131877	SCV000683052	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This variant deletes 4 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 reported in individuals affected with breast cancer and ovarian cancer (PMID: 22006311, 22333603, 22711857, 22762150, 23192404, 23772696, 30702160, 30972954, 31090900; 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031062	SCV000803347	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-22	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047925	SCV000918689	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2679_2682delGAAA (p.Lys893AsnfsX106) 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 250972 control chromosomes. c.2679_2682delGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (ie. Alsop_2012, Couch_1997, Rummel_2013, Roberston_2012, Wagner_1996, etc). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255129	SCV001158346	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	The BRCA1 c.2679_2682delGAAA; p.Lys893AsnfsTer106 variant (rs80357596), also reported as 2798del4, has been described in several individuals with hereditary breast and ovarian syndrome (Azzollini 2016, Borg 2010, Couch 1997, Walsh 2011). This variant is reported in ClinVar (Variation ID: 37481), and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Azzollini J et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. PMID: 27062684. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. PMID: 20104584. Couch F et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409-15. PMID: 9145677. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311.
CeGaT Center for Human Genetics Tuebingen	RCV000255129	SCV001747808	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255129	SCV002017928	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131877	SCV002538147	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	curation
Baylor Genetics	RCV000031062	SCV004215085	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031062	SCV000053657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031062	SCV000144509	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047925	SCV000587245	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031062	SCV005061281	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control