Submissions for variant NM_007294.4(BRCA1):c.5345G>A (p.Trp1782Ter)

dbSNP: rs80357219

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112626	SCV000300245	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112626	SCV000326286	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496911	SCV000605756	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-23	criteria provided, single submitter	clinical testing	The p.Trp1782X (c.5345G>A) variant in BRCA1 has been reported in at least 5 indi viduals with BRCA1-associated cancers (Evans 2003, Breast Cancer Information Cor e (BIC) database) and was absent from large population studies. In addition, a d ifferent nucleotide change (c.5346G>A) resulting in the same amino acid change ( p.Trp1782X) was reported in 15 individuals with BRCA1-associated cancers (Sobcz ak 1997; Machackova 2008; BIC database). This nonsense variant leads to a premat ure termination codon at position 1782, which is predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA1 gene is an estab lished disease mechanism in hereditary breast and ovarian cancer (HBOC). In addi tion, this variant was classified as Pathogenic on September 8, 2016 by the Clin Gen-approved ENIGMA expert panel (ClinVar SCV000300245.2). In summary, the p.Trp 1782X variant meets our criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner.
Ambry Genetics	RCV000575788	SCV000660955	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	The p.W1782* pathogenic mutation (also known as c.5345G>A), located in coding exon 20 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5345. This changes the amino acid from a tryptophan to a stop codon within coding exon 20. This mutation has been detected in multiple individuals with personal and/or family histories of breast and epithelial ovarian cancer (Geisler JP et al. J. Natl. Cancer Inst. 2002 Jan; 94(1):61-7; Evans DG et al. J. Med. Genet. 2003 Sep; 40(9):e107; Nanda R et al. JAMA. 2005 Oct; 294(15):1925-33; Kluska A et al. BMC Med. Genomics. 2015 May; 8:19). Of note, this alteration is also designated as 5464G>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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496911	SCV001583408	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1782*) 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: 12960223, 25948282). This variant is also known as 5464G>A. ClinVar contains an entry for this variant (Variation ID: 55544). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496911	SCV001821273	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5345G>A (p.Trp1782X) 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 251446 control chromosomes. c.5345G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) activity (example, Findlay_2018). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consotrium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001795043	SCV002032749	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of BRCA1-related cancers (Evans 2003, Perkowska 2003, Delgado-Balderas 2018, Rebbeck 2018, Pogoda 2020); 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5464G>A; This variant is associated with the following publications: (PMID: 10788334, 12960223, 11371136, 12673801, 30209399, 31409081, 31173646, 32772980, 32719484, 25948282, 9362443, 32322271, 29997359, Guarneri [case report], 16234499, 11773283, 29446198)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001795043	SCV002047336	pathogenic	not provided	2020-11-12	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 and/or ovarian cancer in the published literature (PMID: 25948282 (2015), 16234499 (2005), 9362443 (1997), 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Therefore, the variant is classified as pathogenic.
Baylor Genetics	RCV000112626	SCV004216861	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112626	SCV000145471	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-06-26	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496911	SCV000587500	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112626	SCV001243146	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro