Submissions for variant NM_007294.4(BRCA1):c.427G>T (p.Glu143Ter)

dbSNP: rs80356991

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031162	SCV000282326	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048511	SCV000076524	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu143*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 20104584, 22009639, 23961350, 24504028). This variant is also known as 546G>T and E143X. ClinVar contains an entry for this variant (Variation ID: 37581). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074592	SCV000108677	pathogenic	not provided	2021-09-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals and families with breast and/or ovarian cancer, and has been reported to be an Irish pathogenic founder variant (van Orsuow 1999, Meyer 2003, van der Hout 2006, Janavicius 2010, Solano 2012, Cunningham 2014, Walsh 2015); Not observed 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 546G>T; This variant is associated with the following publications: (PMID: 32719484, 32338768, 9333265, 29961768, 25525159, 30093976, 29446198, 29506128, 25503966, 18680205, 29422015, 28873162, 25085752, 26733283, 27836010, 28127413, 25673166, 26681312, 25823446, 12938098, 23961350, 20104584, 16683254, 23199084, 24504028, 10528853, 22009639)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031162	SCV000195884	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162876	SCV000213363	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	clinical testing	The p.E143* pathogenic mutation (also known as c.427G>T), located in coding exon 5 of the BRCA1 gene, results from a G to T substitution at nucleotide position 427. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This mutation has been reported in several individuals diagnosed with breast and/or ovarian cancer (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This alteration has been reported to co-occur with the BRCA2 c.8730delT mutation in a Caucasian patient from Denmark (Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). This alteration has also been reported as a possible Irish founder mutation, after the author noted that it accounted for 22% of all HBOC individuals in an Irish population (Janaviius R. EPMA J. 2010 Sep;1:397-412). It has since been reported in multiple individuals from Western Ireland (McVeigh TP et al. Ir. J. Med. Sci. 2014 Jun;183:199-206). Of note, this alteration is also designated as 546G>T 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074592	SCV000296310	pathogenic	not provided	2020-10-13	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast cancer and ovarian cancer in the published literature (PMID: 27836010 (2016), 24504028 (2014), 23961350 (2012), 22009639 (2012), 20104584 (2010)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031162	SCV000325911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162876	SCV000537632	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent protein product and BRCA1 mRNA levels is severely reduced in carrier RNA (PMID: 12393792). A functional study has reported that this variant impacts BRCA1 in ubiquitin E3 ligase assays (PMID: 25823446). This variant has been reported in at least 20 individuals and families affected with breast and ovarian cancer (PMID: 9333265, 12393792, 20104584, 23961350, 23884708, 24504028, 26681312, 26833046, 33471991; Leiden Open Variation Database DB-ID BRCA1_000082; Color internal data) and it is a suspected founder mutation in the Irish population (PMID: 23199084). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). 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.
Baylor Genetics	RCV000465234	SCV000540935	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074592	SCV000885068	pathogenic	not provided	2017-10-19	criteria provided, single submitter	clinical testing	The BRCA1 c.427G>T, p.Glu143Ter variant (rs80356991) has been reported in patients with breast or ovarian cancer (Shattuck-Eidens 1997, Cunningham 2014), and listed as pathogenic on ClinVar (Variation ID: 37581). The predicted truncated BRCA1 protein lacks homologous recombination activity when expressed in yeast (Caligo 2009). The variant is not been observed in the general population databases, such as the 1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the p.Glu143Ter variant is classified as pathogenic. References: Caligo M et al. (2009) Hum Mutat. A yeast recombination assay to characterize human BRCA1 missense variants of unknown pathological significance. 30(1):123-33. Cunningham J et al (2014). Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 4:4026. Shattuck-Eidens D et al (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 278(15):1242-50.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048511	SCV000916796	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.427G>T (p.Glu143X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251024 control chromosomes. c.427G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Solano_2013, Judkins_2005, Evans_2003, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000074592	SCV002067503	pathogenic	not provided	2020-07-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.427G>T, which results in the creation of a premature stop codon at amino acid position 143, p.Glu143*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. This pathogenic sequence change, also reported as c.546G>T in the literature, has previously been described in individuals with breast and/or ovarian cancer, and pancreatic cancer (PMIDs: 9333265, 22009639, 24504028, 20104584, 23961350, 29961768). The p.Glu143* change has not been described in population databases (gnomAD, ExAC). These collective evidences suggest that this sequence change is pathogenic.
Sema4, Sema4	RCV000162876	SCV002538285	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000074592	SCV002545934	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Supporting
Baylor Genetics	RCV000031162	SCV004215106	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000074592	SCV004224927	pathogenic	not provided	2022-06-20	criteria provided, single submitter	clinical testing	PP5, PM2, PS3, PVS1
All of Us Research Program, National Institutes of Health	RCV000031162	SCV004823662	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent protein product and BRCA1 mRNA levels is severely reduced in carrier RNA (PMID: 12393792). A functional study has reported that this variant impacts BRCA1 in ubiquitin E3 ligase assays (PMID: 25823446). This variant has been reported in at least 20 individuals and families affected with breast and ovarian cancer (PMID: 9333265, 12393792, 20104584, 23961350, 23884708, 24504028, 26681312, 26833046, 33471991; Leiden Open Variation Database DB-ID BRCA1_000082; Color internal data) and it is a suspected founder mutation in the Irish population (PMID: 23199084). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048511	SCV004848281	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Glu143X variant in BRCA1 has been reported in >15 individuals with BRCA1-related cancers (Shattuck-Eidens 1997, Caligo 2009, Cunningham 2014, Susswein 2016, Lowery 2018, Yurgelun 2019, BIC database). It was absent from large population studies. This frameshift variant leads to a premature termination codon at position 143, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031162	SCV005046001	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PP3; PS3; PP1_Strong; PM3_Supporting
Sharing Clinical Reports Project (SCRP)	RCV000031162	SCV000053762	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031162	SCV000145476	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048511	SCV000587052	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074592	SCV000591266	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031162	SCV000733673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074592	SCV001959757	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000074592	SCV001975761	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031162	SCV004244171	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing