Submissions for variant NM_007294.4(BRCA1):c.2681_2682del (p.Lys894fs)

dbSNP: rs80357971

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019236	SCV000282287	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	RCV000047927	SCV000075940	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys894Thrfs*8) 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 BRCA1-related conditions (PMID: 7894493, 12698193, 21324516, 22006311, 23199084). It is commonly reported in individuals of European ancestry (PMID: 7894493, 12698193, 21324516, 22006311, 23199084). This variant is also known as 2800delAA. ClinVar contains an entry for this variant (Variation ID: 17667). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074575	SCV000108660	pathogenic	not provided	2023-02-13	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 personal or family history consistent with pathogenic variants in this gene (Friedman et al., 1994; Liede et al., 2000; Couch et al., 2015; Nguyen-Dumont et al., 2018; Frugtniet et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2800delAA; This variant is associated with the following publications: (PMID: 25452441, 26884819, 26681312, 27376475, 26848151, 27456091, 31970404, 34662886, 28888541, 10682686, 21324516, 7894493, 22006311, 23199084, 12698193, 25072261, 25782689, 17688236, 28918466, 25085752, 29435075, 29422015, 29339979, 26295337, 16644204, 23269703, 21702907, 30678073, 30322717, 31159747, 31263054, 33087929, 34657373, 32719484)
Ambry Genetics	RCV000131876	SCV000186931	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	The c.2681_2682delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2681 to 2682, causing a translational frameshift with a predicted alternate stop codon (p.K894Tfs*8). This mutation has been identified in multiple breast and/or ovarian cancer families and has been described as a Scottish founder mutation (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Janavicius R. EPMA J. 2010 Sep;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Wong-Brown M et al. Hered. Cancer Clin. Pract. 2016 Feb;14:6; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan 10;16:3). Of note, this alteration is also designated as 2800delAA 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074575	SCV000296277	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	The BRCA1 c.2681_2682del (p.Lys894Thrfs*8) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 30322717 (2018)), 29422015 (2018), 26884819 (2016), 21324516 (2011), 23199084 (2010), 7894493 (1994)). It has been described as a founder mutation in the Scottish/Irish populations (PMIDs: 12698193 (2003) and 23199084 (2010)). The variant has also been reported in prostate cancer (PMID: 27456091 (2016)), peritoneal cancer (PMID: 22006311 (2011)), as well as in colorectal cancer (PMID: 26681312 (2015)). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019236	SCV000325427	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019236	SCV000564364	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000019236	SCV000593682	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-11-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047927	SCV000605755	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Lys894ThrfsX8 variant in BRCA1 has been reported in >80 individuals with BRCA1-associated cancers (Friedman 1994, Walsh 2011, Wong-Brown 2016, Zhang 2011, Liede 2000, Breast Cancer Information Core (BIC) database), segregated with disease in >10 affected relatives, and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282287.1). In summary, the p.Lys894fs variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2.
Counsyl	RCV000019236	SCV000677644	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131876	SCV000683053	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-14	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 reported in over ten individuals affected with breast or ovarian cancer (PMID: 7791869, 7894493, 16644204, 21324516, 25452441, 29422015, 33471991; Leiden Open Variation Database DB-ID BRCA1_001657), including observed co-segregation with breast and ovarian cancer in 8 members of one family across multiple generations (PMID: 7894493). This variant also has been reported in one individual each affected with peritoneal and colorectal cancer (PMID: 22006311, 26681312). This variant has been reported as a founder mutation in the individuals with Scottish ancestry (PMID: 10682686, 12698193). 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.
GeneKor MSA	RCV000019236	SCV000693521	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes two bases from exon 10 of the BRCA1 mRNA (c.2681_2682delAA ) causing a frameshift after codon 894 and the creation of a premature translation stop signal 8 amino acid residues later p.(Lys894Thrfs). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). This mutation has been described in the mutation database ClinVar (Variation ID:17667) .
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047927	SCV000698972	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-10	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2681_2682delAA (p.Lys894Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.2685_2686delAA, c.2719_2722delGAAG, c.2766delA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121670 control chromosomes. The variant has been reported in the literature and databases in numerous affected individuals, and is considered a European founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Division of Medical Genetics, University of Washington	RCV000019236	SCV001424799	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-08-09	criteria provided, single submitter	clinical testing	This variant leads to a translational frameshift and the introduction of a premature termination codon 8 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of BRCA1 is a well-established mechanism of disease for hereditary breast and ovarian cancer. This variant has been reported in multiple individuals and families with breast and/or ovarian cancer, and is considered a European founder variant (Liede 2000, Scottish/Northern Irish BRCAI/BRCA2 Consortium 2003, Hondow 2011, Walsh 2011, Zhang 2011). Thus, this variant is interpreted as pathogenic.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000047927	SCV002522171	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131876	SCV002538150	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000019236	SCV003928094	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	The BRCA1 c.2681_2682del (p.Lys894ThrfsTer8) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant, which is also known as 2800delAA in published literature, has been reported in several individuals with HBOC-related cancers (PMID: 7894493, 27456091, 22006311, 21324516, 33758026, 34657373) and has also been reported as a Scottish founder mutation (PMID: 10682686). This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics	RCV000019236	SCV004212691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-22	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000047927	SCV004228024	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing
OMIM	RCV000019236	SCV000039524	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019236	SCV000053658	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019236	SCV000144511	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	RCV000047927	SCV000587246	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074575	SCV000591404	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Lys894ThrfsX8 variant was identified in 19 of 6162 proband chromosomes (frequency: 0.03) from individuals or families with breast and epithelial ovarian cancers, and was not identified in 3810 control chromosomes from healthy individuals. The variant has been identified as a Scottish and northern Irish founder mutation (Song_2014, Janavicius_2010, Consortium_2003, Nanda_2005, Peto_1999). The variant was also identified in dbSNP (ID: rs80357971) as “With Pathogenic allele” and in Clinvar and Clinvitae as pathogenic by Evidence-based Network for the interpretation of Germline Mutant Alleles (ENIGMA) Study description; Quest Diagnostics Nichols Institute San Jaun Capistrano; the Consortium of Investigators of Modifiers of BRCA1/2 Univeristy of Cambridge, Ambry Genetics; Invitae; GeneD;, Breast Cancer Informatin Core; OMIM and Sharing Clinical Reports project. The variant has been further identified in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was not identified in LOVD-IARC, COSMIC, GeneInsight COGR, the BIC, UMD and Fanconi Anemia Mutation (LOVD) and The Exome Aggregation Consortium databases (August 8, 2016) nor was it identified in the 1000 Genomes Project, and the NHLBI GO Exome Sequencing Project. The p.Lys894ThrfsX8 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 894 and leads to a premature stop codon 8 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735499	SCV000863637	pathogenic	Breast and/or ovarian cancer	2003-09-24	no assertion criteria provided	clinical testing