ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3481_3491del (p.Glu1161fs) (rs80357877)

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Total submissions: 21
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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) RCV000019254 SCV000282308 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 RCV000048211 SCV000076224 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1161Phefs*3) 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 in individuals with a personal and family history of breast and ovarian cancer (PMID: 7611277, 12955716, 10196379), and is a well-known founder mutation in the French population (PMID: 15131401, 23199084). This variant is also known as 3600del11 and 3600_3610del11 in the literature. ClinVar contains an entry for this variant (Variation ID: 17684). 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 RCV000131815 SCV000186870 pathogenic Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000159917 SCV000210040 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This deletion of 11 nucleotides in BRCA1 is denoted c.3481_3491del11 at the cDNA level and p.Glu1161PhefsX3 (E1161FfsX3) at the protein level. The surrounding sequence is AAAG[del11]TTTTG. The deletion causes a frameshift, which changes a Glutamic Acid to a Phenylalanine at codon 1161 and creates a premature stop codon at position 3 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. This variant, also denoted as BRCA1 3600del11 using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer and is considered to be a pathogenic founder variant in France (Struewing 1995, Diez 2003, Muller 2004, de Juan Jimenez 2013). Based on currently available information, we consider this to be a pathogenic variant.
Counsyl RCV000019254 SCV000220697 pathogenic Breast-ovarian cancer, familial 1 2014-09-16 criteria provided, single submitter literature only
Color RCV000131815 SCV000292140 pathogenic Hereditary cancer-predisposing syndrome 2015-01-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159917 SCV000296335 pathogenic not provided 2015-05-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019254 SCV000325665 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048211 SCV000605744 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-04 criteria provided, single submitter clinical testing The p.Glu1161fs variant in BRCA1 has been reported as a founder variant in the F rench population (Muller 2004, Janavicius 2010) that has been observed in more t han >70 individuals with BRCA1-associated cancers (Struewing 1995, Janezic 1999, Muller 2004, Breast Cancer Information Core (BIC) database). It was also absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1161 and l eads to a premature termination codon 3 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 for hereditary b reast and ovarian cancer (HBOC). Additionally, the p.Glu1161fs variant was class ified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert pane l (ClinVar SCV000282308.1). In summary, this variant meets our criteria to be cl assified as pathogenic for autosomal dominant HBOC.
Integrated Genetics/Laboratory Corporation of America RCV000048211 SCV000699037 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-24 criteria provided, single submitter clinical testing Variant summary:The BRCA1 c.3481_3491delGAAGATACTAG (p.Glu1161fsPheX3) variant results in a premature termination codon in exon 10, 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. p.Glu1134X, p.Gln1135X, p.Glu1221X, etc.). This variant is absent in 246046 control chromosomes (gnomAD). The variant has been recurrently reported in HBOC patients/families in literature, clinical databases and labs. Several clinical labs/databases have classified it as pathogenic. Taken together, this variant is classified as Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000019254 SCV000744633 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000048211 SCV000839254 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159917 SCV000858441 pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing
OMIM RCV000019254 SCV000039542 pathogenic Breast-ovarian cancer, familial 1 1999-05-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019254 SCV000053708 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019254 SCV000144774 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000019254 SCV000189884 pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000019254 SCV000211998 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048211 SCV000587313 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000159917 SCV000778746 pathogenic not provided 2017-12-07 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785408 SCV000923980 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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