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

gnomAD frequency: 0.00001  dbSNP: rs80356962

Total submissions: 32

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, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167788	SCV000077009	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 21922593). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 55580). This variant is also known as 5563G>A. This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 8968102, 20104584, 26187060). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1815*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the BRCA1 protein.
GeneDx	RCV000048996	SCV000210221	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation 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 (Montagna 1996, Kang 2002, Borg 2010, Jalkh 2012, Fernandes 2016); Not observed at significant frequency 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 5563G>A; This variant is associated with the following publications: (PMID: 29961768, 30209399, 25400221, 26681312, 29446198, 29797126, 15365993, 16267036, 24131973, 28492532, 23469205, 24884479, 20104584, 19996028, 22798144, 32658311, 32039725, 33558524, 27741520, 8968102, 12204006, 22713736, 29998185)
Ambry Genetics	RCV000162887	SCV000213374	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-06	criteria provided, single submitter	clinical testing	The p.W1815* pathogenic mutation (also known as c.5444G>A), located in coding exon 21 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5444. This changes the amino acid from a tryptophan to a stop codon within coding exon 21. This mutation has been detected in multiple breast and/or ovarian cancer patients and has been observed to segregate with disease in affected families (Montagna M et al. Cancer Res., 1996 Dec;56:5466-9; Kang HC et al. Hum. Mutat., 2002 Sep;20:235; Seo JH et al. Hum. Mutat., 2004 Oct;24:350; Oktay K et al. J Clin Oncol, 2010 Jan;28:240-4; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Jalkh N et al. Hered Cancer Clin Pract, 2012 Jun;10:7; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Safra T et al. Ann Oncol, 2013 Nov;24 Suppl 8:viii63-viii68; Silva FC et al. BMC Med Genet, 2014 May;15:55; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Kechin AA et al. Bull Exp Biol Med, 2018 May;165:94-100; Matsuo K et al. Gynecol Oncol Rep, 2018 Aug;25:98-101; Bernstein-Molho R et al. Breast Cancer Res Treat, 2019 Nov;178:231-237; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This mutation was also detected in at least one patient with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223). Of note, this alteration is also designated as 5563G>A 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. As such, this alteration is interpreted as a disease-causing mutation
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112656	SCV000267720	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414344	SCV000492458	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Counsyl	RCV000112656	SCV000677662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167788	SCV000699254	pathogenic	Hereditary breast ovarian cancer syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000167788	SCV000839208	pathogenic	Hereditary breast 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, susceptibility to, 1; Pancreatic cancer, susceptibility to, 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	This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in individuals with suspected hereditary breast and/or ovarian cancer in the published literature (PMID: 29998185 (2018), 29797126 (2018), 26681312 (2015), 20104584 (2010), 8968102 (1996)). Therefore, this individual is at increased risk of developing BRCA1 related cancers.
Color Diagnostics, LLC DBA Color Health	RCV000162887	SCV001354792	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 22 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 8968102, 20104584, 22798144, 29998185, 31368036, 32658311, 33558524) and pancreatic cancer (PMID: 29961768). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000048996	SCV001447108	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000048996	SCV001449780	pathogenic	not provided	2014-10-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000048996	SCV001502244	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735516	SCV002043459	pathogenic	Breast and/or ovarian cancer	2020-01-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000048996	SCV003811744	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048996	SCV004026744	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000112656	SCV004215079	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112656	SCV004817542	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 22 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 8968102, 20104584, 22798144, 29998185, 31368036, 32658311, 33558524) and pancreatic cancer (PMID: 29961768). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112656	SCV000145516	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112656	SCV000297621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 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 ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353974	SCV000591633	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Trp1815X variant was identified in at least 7 of 115778 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Borg 2010, Jalkh 2012, Judkins 2005, Kang 2002, Montagna 1996, Oktay 2010). The variant was also identified in dbSNP (ID: rs80356962) “With untested allele”, HGMD, UMD (2X as a causal variant), and the BIC database (4X with clinical importance). The p.Trp1815X variant leads to a premature stop codon at position 1815, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
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, University Hospital Cologne	RCV000785212	SCV000923780	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Center of Medical Genetics and Primary Health Care	RCV000167788	SCV000987236	pathogenic	Hereditary breast 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.
Brotman Baty Institute, University of Washington	RCV000112656	SCV001243337	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554250	SCV001774814	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112656	SCV002588838	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing