Submissions for variant NM_007294.4(BRCA1):c.1916T>A (p.Leu639Ter)

dbSNP: rs80357267

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083175	SCV000282267	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.
Ambry Genetics	RCV000131894	SCV000186949	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The p.L639* pathogenic mutation (also known as c.1916T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 1916. This changes the amino acid from a leucine to a stop codon within coding exon 9. This pathogenic variant has been reported in numerous families diagnosed with breast and/or ovarian cancer (Gayther SA et al. Nat. Genet.,1995 Dec;11:428-33; Hoyer J et al. BMC Cancer. 2018 Sep;18:926; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). 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.
GeneDx	RCV000212165	SCV000210115	pathogenic	not provided	2015-04-20	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.1916T>A at the cDNA level and p.Leu639Ter (L639X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also referred to as 2035T>A using alternate nomenclature, has been reported in Hereditary Breast and Ovarian Cancer families and is considered pathogenic (Gayther 1995).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083175	SCV000325180	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212165	SCV001133503	pathogenic	not provided	2019-03-22	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Invitae	RCV000496730	SCV001579952	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu639*) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 7493024, 29446198, 30257646). ClinVar contains an entry for this variant (Variation ID: 54399). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000083175	SCV004215123	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083175	SCV000115249	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-05-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083175	SCV000144249	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496730	SCV000587167	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research