Submissions for variant NM_007294.4(BRCA1):c.963G>A (p.Trp321Ter)

dbSNP: rs886040335

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257375	SCV000323940	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	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	RCV000257375	SCV000326475	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000637520	SCV000758982	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 266597). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp321*) 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).
Ambry Genetics	RCV001019582	SCV001180961	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The p.W321* pathogenic mutation (also known as c.963G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 963. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This amino acid change has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Shattuck-Eidens D et al. JAMA. 1997;278(15):1242-50, Oros KK et al. Int J Cancer. 2004;112(3):411-9, Walsh T et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-7; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601). A different nucleotide change was reported in two of these cases (c.962G>A/1081G>A) but the resulting amino acid change was the same. Of note, this alteration is also referred to as 1082G>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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000637520	SCV003923028	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.963G>A (p.Trp321X) 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 251402 control chromosomes (gnomAD). c.963G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer from Hereditary Breast And Ovarian Cancer Syndrome families (e.g. Thorstenson_2003, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. This variant also results in the same amino acid change as a previously established pathogenic variant (c.962G>A, p.W321X), providing further evidence in support of pathogenicity. Five submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477876	SCV004219483	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with hereditary breast and/or ovarian cancer (HBOC) (PMID: 32295079 (2020)). Based on the available information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735518	SCV000863656	pathogenic	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000735518	SCV001451790	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000257375	SCV003927208	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic variant was detected in the BRCA1 gene (c.963G>A). This sequence change creates a premature translational stop signal (p.Trp321*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 266597) with 6 submissions, all of which describe it as pathogenic, three stars, reviewed by expert panel. A different variant (c.962G>A) giving rise to the same protein effect observed here (p.Trp321*) has been reported in individuals affected with hereditary breast and ovarian cancer (PMID: 26976419, 28503720, 22006311, 9333265, 22535016, 10644434). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). In-silico predictions show pathogenic computational verdict based on 5 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL and MutationTaster vs no benign predictions. Therefore, this variant has been classified as Pathogenic