Submissions for variant NM_007294.4(BRCA1):c.4523G>A (p.Trp1508Ter)

dbSNP: rs786202631

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241110	SCV000300133	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.
Ambry Genetics	RCV000165536	SCV000216268	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-15	criteria provided, single submitter	clinical testing	The p.W1508* pathogenic mutation (also known as c.4523G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4523. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome patients families to date (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80; Laitman et al. Breast Cancer Res. Treat. 2011 Jun;127(2):489-95; Walsh T et al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000508652	SCV000605881	pathogenic	not provided	2016-12-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000508652	SCV000617445	pathogenic	not provided	2021-08-09	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; 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 c.4642G>A; This variant is associated with the following publications: (PMID: 31090900, 27221827, 20960228, 22009639, 23982851, 26250392, 23192404, 25682074)
Color Diagnostics, LLC DBA Color Health	RCV000165536	SCV000905201	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast and ovarian cancer (PMID: 22006311, 25682074, 29021639; Color internal data), and a suspected hereditary breast and ovarian cancer family (PMID: 26250392). A different mutation c.4524G>A resulting in a premature termination at codon 1508 also has been reported in an individual affected with breast cancer (PMID: 27082205) and two suspected hereditary breast and ovarian cancer families (PMID: 20960228, 31409081). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793994	SCV000933376	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-26	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: 186016). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25682074). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1508*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000793994	SCV001364032	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4523G>A (p.Trp1508X) 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. The variant was absent in 251348 control chromosomes (gnomAD). c.4523G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Briceno-Balcazar_2017, Judkins_2005, Lynce_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions including an expert panel, ENIGMA, (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV003398845	SCV004123116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2023-11-07	criteria provided, single submitter	clinical testing