ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3752_3755GTCT[1] (p.Ser1253fs) (rs80357868)

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Total submissions: 26
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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) RCV000019242 SCV000282317 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 RCV000167859 SCV000076327 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1253Argfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357868, ExAC 0.004%). This variant has been reported in individuals affected with breast and/or ovarian cancer, and pancreatic cancer (PMID: 7894491, 21324516, 23633455, 21989927). This variant is also known as 3875del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 17673). 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 RCV000131810 SCV000186865 pathogenic Hereditary cancer-predisposing syndrome 2018-03-21 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 RCV000048314 SCV000210046 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA1 is denoted c.3756_3759delGTCT at the cDNA level and p.Ser1253ArgfsX10 (S1253RfsX10) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GTCT[delGTCT]AAGA. The deletion causes a frameshift, which changes a Serine to an Arginine at codon 1253, and creates a premature stop codon at position 10 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.3756_3759delGTCT, also denoted 3875del4 using alternate nomenclature, has been published in association with breast and ovarian cancers (Castilla 1994, Zhang 2011, Alsop 2012, Gaj 2012, Ghiorzo 2012, George 2013). This variant is also a well-described pathogenic founder variant in the French-Canadian population in Quebec (Janavicius 2010). We consider this variant to be pathogenic.
Counsyl RCV000019242 SCV000220913 likely pathogenic Breast-ovarian cancer, familial 1 2014-11-24 criteria provided, single submitter literature only
Color RCV000131810 SCV000292139 pathogenic Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048314 SCV000296325 pathogenic not provided 2015-04-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000239051 SCV000296799 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019242 SCV000325742 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000019242 SCV000564358 pathogenic Breast-ovarian cancer, familial 1 2015-02-10 criteria provided, single submitter clinical testing
Genologica Medica RCV000019242 SCV000577928 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167859 SCV000591471 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000167859 SCV000699069 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3756_3759delGTCT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1756fs). Mutation Taster predicts a damaging outcome for this variant. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in multiple HBOC patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000019242 SCV000744625 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000019242 SCV000839892 pathogenic Breast-ovarian cancer, familial 1 2017-11-01 criteria provided, single submitter clinical testing The c.3756_3759delGTCT (p.Ser1253Argfs*10) frame shift variant is predicted to yield loss of function transcripts/proteins of BRCA1 gene, which is one of mechanisms causing BRCA1 defect related cancers. This variant is extremely rare in general population (4 in 246010 by gnomad) and observed in multiple breast/ovarian cancer patients (PMID:78944991, 12947551, 21324516, 23633455, 24504028). It has been also observed in other clinical labs and reported as pathogenic. Based on the above evidences, we interpret this variant as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019242 SCV000993437 pathogenic Breast-ovarian cancer, familial 1 2019-06-25 criteria provided, single submitter research
OMIM RCV000019242 SCV000039530 pathogenic Breast-ovarian cancer, familial 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019242 SCV000053723 pathogenic Breast-ovarian cancer, familial 1 2013-11-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019242 SCV000144861 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000019242 SCV000212000 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000239051 SCV000484932 pathogenic Familial cancer of breast no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167859 SCV000587342 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019242 SCV000733618 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735506 SCV000863644 pathogenic Breast and/or ovarian cancer 2015-05-19 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000782127 SCV000916304 pathogenic breast cancer no assertion criteria provided clinical testing The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented ?with untested allele? (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785410 SCV000923982 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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