ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5444G>A (p.Trp1815Ter) (rs80356962)

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Total submissions: 22
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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) RCV000112656 SCV000300259 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000167788 SCV000077009 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal within the penultimate exon of the BRCA1 mRNA at codon 1815 (p.Trp1815*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 49 amino acids of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families affected with hereditary breast and/or ovarian cancer, segregating with disease in a family (PMID: 8968102, 26187060, 20104584). It is also known as 5563G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55580). This variant has been reported to create a truncated BRCA1 protein that is expected to result in loss of a portion of the C-terminal BRCT-C functional domain (PMID: 8968102). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000048996 SCV000210221 pathogenic not provided 2015-06-26 criteria provided, single submitter clinical testing This is a nonsense variant, denoted BRCA1 c.5444G>A at the cDNA level and p.Trp1815Ter (W1815X) at the protein level. The substitution creates a nonsense variant, changing a Tryptophan to a premature stop codon (TGG>TAG). This variant is predicted to cause loss of normal protein function through protein truncation. This variant, also denoted as 5563G>A using alternate nomenclature, has been reported in association with breast and ovarian cancer (Montagna 1996).
Ambry Genetics RCV000162887 SCV000213374 pathogenic Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Michigan Medical Genetics Laboratories,University of Michigan RCV000112656 SCV000267720 pathogenic Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112656 SCV000326313 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000414344 SCV000492458 pathogenic Neoplasm of the breast criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167788 SCV000591633 pathogenic Hereditary breast and ovarian cancer syndrome 2014-04-16 criteria provided, single submitter clinical testing
Counsyl RCV000112656 SCV000677662 pathogenic Breast-ovarian cancer, familial 1 2016-12-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000162887 SCV000693545 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1815 of the BRCA1 protein. It is expected to result in loss of a portion of the C-terminal BRCT-C functional domain (PMID: 8968102). Truncating variants in BRCA1 gene are known to be pathogenic. This particular variant has been described in the literature in multiple individuals and families affected with hereditary breast and/or ovarian cancer, segregating with disease in a family (PMID: 8968102, 26187060, 20104584). The mutation database ClinVar contains entries for this variant (Variation ID: 55580).
Integrated Genetics/Laboratory Corporation of America RCV000167788 SCV000699254 pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-21 criteria provided, single submitter clinical testing
Mendelics RCV000167788 SCV000839208 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763398 SCV000894124 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048996 SCV001133633 pathogenic not provided 2018-12-22 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, 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.
Color RCV000162887 SCV001354792 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112656 SCV000145516 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112656 SCV000297621 pathogenic Breast-ovarian cancer, familial 1 2008-03-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167788 SCV000587509 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 RCV000735516 SCV000863654 pathogenic Breast and/or ovarian cancer 2014-01-20 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785212 SCV000923780 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Center of Medical Genetics and Primary Health Care RCV000167788 SCV000987236 pathogenic Hereditary breast and ovarian cancer syndrome 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria BRCA1 (NM_007294.3: c.5444G>A; p.Trp1815Ter) - The BRCA1 variant p.Trp1815Ter is a known pathogenic nonsense variant in exon 23 and in the functional domain of BRCT2 (aa 1756-1855). BRCA1 contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). This null (nonsense) variant is predicted to encode a truncated non-functional protein which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant was observed in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (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 SCV000300259.2) (PP5 Pathogenic Supporting). 4 pathogenic predictions from DANN, EIGEN, FATHMM-MKL and MutationTaster versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was seen in 4 unrelated patients with a unilateral breast cancer and a strong family history of breast cancer. Therefore, this variant was classified as a Pathogenic (Table 1).
Brotman Baty Institute,University of Washington RCV000112656 SCV001243337 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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