ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4035del (p.Glu1346fs) (rs80357711)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130638 SCV000185517 pathogenic Hereditary cancer-predisposing syndrome 2018-01-18 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)
Breast Cancer Information Core (BIC) (BRCA1) RCV000031141 SCV000144938 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130638 SCV000683145 pathogenic Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031141 SCV000325817 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031141 SCV000221052 pathogenic Breast-ovarian cancer, familial 1 2015-01-19 criteria provided, single submitter literature only
Department of Medical Genetics,Oslo University Hospital RCV000031141 SCV000564320 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048413 SCV000591480 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-13 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000048413 SCV000588051 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031141 SCV000282321 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000074587 SCV000108672 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.4035delA at the cDNA level and p.Glu1346LysfsX20 (E1346KfsX20) at the protein level. The normal sequence, with the deleted base in brackets, is ATGA[delA]GAAA. The deletion causes a frameshift, changing a Glutamic Acid to a Lysine at codon 1346, and creating a premature stop codon at position 20 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. BRCA1 c.4035delA, also reported as 4153delA or 4154delA using alternate nomenclature, has been observed in association with breast and/or ovarian cancer and is reported as a pathogenic founder variant in several eastern European countries (Gayther 1996, Bogdanova 2010, Janavicius 2013, Szwiec 2015, Synowiec 2016). We consider this variant to be pathogenic.
GeneKor MSA RCV000239274 SCV000296800 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031141 SCV000993554 pathogenic Breast-ovarian cancer, familial 1 2019-02-04 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000048413 SCV000699099 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4035delA (p.Glu1346Lysfs) variant (alternatively also known as c.4034delA, 4153delA and 4154delA) results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate two BCRT domains (InterPro) that are known to be critical for BRCA1 function. Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Glu1373X, p.Gln1395X, p.Gln1408X, etc.). This variant was found in 7/123408 control chromosomes including broad and large populations from ExAC at a frequency of 0.0000567, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant is a common pathogenic variant that causes HBOC and has also been reported as a found mutation in east European patients (Bogdanova_2010, Plakhins_2011). In a survival analysis (Plakhins_2011) from HBOC patients from Latvia, the mean estimated survival time during a 20 year follow-up period was calculated as 134 months (95% CI = 92.58 to 177.00) in the c.4035delA group in comparison with 189 months in the c.5266dupC group (95% CI = 166.75 to 211.43) and 192 months in the control group that includes included breast cancer patients who were tested negative for the BRCA1 founder mutations (95% CI = 175.54 to 208.83). As this variant is a common pathogenic variant, the heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000048413 SCV000076426 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1346Lysfs*20) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357711, ExAC 0.007%). This variant is a known common cause of breast and ovarian cancer in individuals from Eastern Europe (PMID: 23199084, 20569256, 20345474, 22032251). In addition, this variant has been associated with a higher prevalence of ovarian cancer than breast cancer (PMID: 22032251, 15591272). This variant is also known as 4153delA and 4154delA in the literature. ClinVar contains an entry for this variant (Variation ID: 37560). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048413 SCV000605754 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-04 criteria provided, single submitter clinical testing The p.Glu1346fs variant in BRCA1 has been reported in >100 individuals with BRCA 1-associated cancers and is a known eastern European founder mutation (Janaviciu s 2013, Tihomirova 2014, Breast Cancer Information Core (BIC) database). This va riant has been identified in 5/66724 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80357711); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is pred icted to cause a frameshift, which alters the protein?s amino acid sequence begi nning at position 1346 and leads to a premature termination codon 20 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 disea se mechanism in individuals with HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Cli nVar SCV000282321.1). In summary, the p.Glu1346fs variant meet criteria to be cl assified as pathogenic for HBOC in an autosomal dominant manner.
OMIM RCV000031141 SCV000039547 pathogenic Breast-ovarian cancer, familial 1 1996-03-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074587 SCV000296398 pathogenic not provided 2016-04-02 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048413 SCV000587366 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031141 SCV000053740 pathogenic Breast-ovarian cancer, familial 1 2013-04-19 no assertion criteria provided clinical testing

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