ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2681_2682del (p.Lys894fs) (rs80357971)

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Total submissions: 20
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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 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 and ovarian cancer syndrome 2019-12-19 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a European founder mutation, also known as 2800delAA (PMID: 7894493, 22006311, 21324516, 12698193, 23199084). ClinVar contains an entry for this variant (Variation ID: 17667). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074575 SCV000108660 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA1 is denoted c.2681_2682delAA at the cDNA level and p.Lys894ThrfsX8 (K894TfsX8) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delAA]CAAA. The deletion causes a frameshift, which changes a Lysine to a Threonine at codon 894 and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2681_2682delAA, also known as c.2681_2682del and 2800delAA by alternate nomenclature, has been published as a founder pathogenic variant in Scotland/Ireland, and has been identified in association with hereditary breast and ovarian cancer (Friedman 1994, Liede 2000, Couch 2015, Nguyen-Dumont 2018). We consider this variant to be pathogenic.
Ambry Genetics RCV000131876 SCV000186931 pathogenic Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074575 SCV000296277 pathogenic not provided 2019-07-16 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 symptomatic patient, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019236 SCV000325427 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000019236 SCV000564364 pathogenic Breast-ovarian cancer, familial 1 2015-06-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047927 SCV000591404 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000019236 SCV000593682 pathogenic Breast-ovarian cancer, familial 1 2016-11-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000047927 SCV000605755 pathogenic Hereditary breast and 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 1 2017-02-01 criteria provided, single submitter clinical testing
Color RCV000131876 SCV000683053 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000019236 SCV000693521 pathogenic Breast-ovarian cancer, familial 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) .
Integrated Genetics/Laboratory Corporation of America RCV000047927 SCV000698972 pathogenic Hereditary breast and 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 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.
OMIM RCV000019236 SCV000039524 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019236 SCV000053658 pathogenic Breast-ovarian cancer, familial 1 2012-06-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019236 SCV000144511 pathogenic Breast-ovarian cancer, familial 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 and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
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

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