Submissions for variant NM_007294.4(BRCA1):c.962G>A (p.Trp321Ter)

dbSNP: rs80357292

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031293	SCV000299514	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.
Invitae	RCV000049204	SCV000077217	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-22	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs80357292, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 10644434, 15382066, 16287141, 16683254, 22535016). This variant is also known as 1081G>A. ClinVar contains an entry for this variant (Variation ID: 37712). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000159948	SCV000210095	pathogenic	not provided	2023-02-06	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 individuals with a personal or family history consistent with pathogenic variants in this gene (Shattuck-Eidens et al., 1997; Walsh et al., 2011; Belanger et al., 2015; Tung et al., 2016; Meric-Bernstam et al., 2016; Nguyen-Dumont et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1081G>A; This variant is associated with the following publications: (PMID: 25722380, 26659639, 9333265, 22535016, 25884701, 22006311, 10644434, 26787237, 27150160, 27376475, 26976419, 27836010, 16905680, 28503720, 25525159, 32719484, 32885271, 30078507, 29446198, 30720243, 30787465, 32467295, 29922827, 30257646, 28888541, 33804961)
Ambry Genetics	RCV000162891	SCV000213378	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	The p.W321* pathogenic mutation (also known as c.962G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 962. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This mutation has been reported in multiple families affected with breast cancer (Shattuck-Eidens D et al. JAMA.1997;278(15):1242-50; Oros KK et al. Int J Cancer. 2004;112(3):411-9; Hoyer J et al. BMC Cancer 2018 Sep;18:926). This alteration has also been described as a French-Canadian founder mutation (Janaviius R. EPMA J 2010 Sep;1(3):397-412), and in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated 1081G>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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735517	SCV000219201	pathogenic	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159948	SCV000296300	pathogenic	not provided	2020-08-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. It has been reported in multiple individuals with hereditary breast and/or ovarian cancer in the published literature (PMIDs: 30257646 (2018), 29446198 (2018), 23772696 (2014), 22535016 (2012), 23199084 (2010), 16905680 (2007), 16683254 (2006), 16287141 (2005), 15728167 (2005), 15382066 (2004), and 9333265 (1997)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000239176	SCV000296788	pathogenic	not specified	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031293	SCV000326474	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162891	SCV000911645	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals and families affected with breast, ovarian and peritoneal cancers (PMID: 9333265, 10644434, 15382066, 16287141, 16683254, 22006311, 22535016, 30257646) and it is described as a recurrent founder mutation in the French-Canadian population (PMID: 23199084). This variant has been identified in 1/251402 chromosomes 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159948	SCV001450201	pathogenic	not provided	2016-09-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159948	SCV003809213	pathogenic	not provided	2022-06-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031293	SCV004215115	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031293	SCV000053898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031293	SCV000143965	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000049204	SCV000587090	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735517	SCV000863655	pathogenic	Breast and/or ovarian cancer	2016-02-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159948	SCV001554359	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Trp321X variant was identified in 4 of 4476 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Shattuck-Eidens 1997, Claus 2005, Belanger 2015, Simard 2007). The variant was also identified in dbSNP (ID: rs80357292) “With Pathogenic allele”, ClinVar (as pathogenic by ENIGMA, CIMBA, Invitae, GeneDx, Ambry Genetics, CHEO, Quest Diagnostics, GeneKor, SCARP, BIC), LOVD 3.0 (4x, functional affect is reported and concluded.), UMD-LSDB (10 records, as class 5, causal), BIC Database (23x reported), and ARUP Laboratories (as class 5 and-Definitely pathogenic). The variant was not identified in Genesight-COGR, Cosmic, MutDB, and Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 246166 chromosomes at a frequency of 0.000004 in European population (Genome Aggregation Consortium Feb 27, 2017). The p.Trp321X variant leads to a premature stop codon at position 321, 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 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.
BRCAlab, Lund University	RCV000031293	SCV004244140	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing