ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.798_799del (p.Ser267fs) (rs80357724)

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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) RCV000031279 SCV000282350 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 RCV000167858 SCV000077154 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser267Lysfs*19) 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 to segregate with breast cancer in one family (PMID: 21603858), and has been seen in several individuals and families affected with breast and/or ovarian cancer (PMID: 7493024, 21324516, 2206311, 26010302, 23233716, 17221156, 18159056). This variant has been described as a founder mutation in individuals and families from North Africa including Tunisia, Algeria, and Morocco (PMID: 25814778, 24312913, 21603858, 26864382, 18645608, 23289006). This variant is also known as 917delTT and 916delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 37698). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131867 SCV000186922 pathogenic Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing The c.798_799delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides between positions 798 and 799, causing a translational frameshift with a predicted alternate stop codon (p.S267Kfs*19). This mutation has previously been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Mahfoudh W et al. Mol. Biol. Rep. 2012 Feb;39(2):1037-46; Laraqui A et al. Int. J. Med. Sci. 2013 Dec;10(1):60-7; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). It was also seen in a pancreatic cancer cohort (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 916delTT 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.
GeneDx RCV000049141 SCV000210004 pathogenic not provided 2021-03-03 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 described as a North African founder variant (Walsh 2011, Uhrhammer 2008, Mahfoudh 2012, Laraqui 2013, De Brakeleer 2015); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 917_918delTT; This variant is associated with the following publications: (PMID: 22006311, 31921681, 28776284, 7493024, 22684231, 25814778, 18645608, 21324516, 15829246, 22425665, 22460208, 26010302, 26864382, 22866093, 27446417, 28212807, 27225819, 26320393, 25780794, 21603858, 23289006, 28478614, 27062684, 29907814, 30606148, 29506128, 31454914, 31447099)
Counsyl RCV000031279 SCV000220420 likely pathogenic Breast-ovarian cancer, familial 1 2014-06-17 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000049141 SCV000296319 pathogenic not provided 2019-04-16 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 RCV000031279 SCV000326412 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506072 SCV000602682 pathogenic not specified 2016-09-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131867 SCV000683359 pathogenic Hereditary cancer-predisposing syndrome 2020-08-17 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 numerous individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 21603858, 23289006, 24312913, 24606420, 25814778, 27062684, 29907814) and is thought to be a founder mutation in the Mediterranean population (PMID: 24312913, 24606420). 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.
Mendelics RCV000167858 SCV000839294 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167858 SCV000918737 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.798_799delTT (p.Ser267LysfsX19) 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 250012 control chromosomes. c.798_799delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000167858 SCV000967733 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-01 criteria provided, single submitter clinical testing The p.Ser267fs variant in BRCA1 has been reported in over 30 individuals with he reditary breast and/or ovarian cancer (HBOC), segregated with disease in one fam ily, and is reported to be a North African founder variant (Laraqui 2013, Mahfou dh 2012, Cherbal 2010, BIC database: https://research.nhgri.nih.gov/bic/). This variant was absent from large population studies. It is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 26 7 and leads to a premature termination codon 19 amino acids downstream. This alt eration 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 indiv iduals with HBOC. In addition, this variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235 0.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, presence in multiple affected individuals, and predicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; PS4; PM2.
Mendelics RCV000031279 SCV001140621 pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659916 SCV001877493 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031279 SCV000053884 pathogenic Breast-ovarian cancer, familial 1 2012-05-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031279 SCV000145687 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 RCV000167858 SCV000587077 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 RCV000735510 SCV000863648 pathogenic Breast and/or ovarian cancer 1997-05-22 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001004847 SCV000987228 pathogenic Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria The BRCA1 p.Ser267Lysfs is a known pathogenic frameshift variant in exon 11 in a non-functional domain just before the serine-rich domain (A344-507R aa) and many other downstream domains. This null variant (frame-shift) is predicted to encode a truncated non-functional protein, and heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). It is found in a mutational hotspot of 29 pathogenic variants (PM1 Pathogenic Moderate). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00028235.01) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 56-year- old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.
CZECANCA consortium RCV000735510 SCV001451788 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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