Submissions for variant NM_007294.4(BRCA1):c.4999A>T (p.Lys1667Ter)

dbSNP: rs80357204

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)	RCV000112459	SCV000300182	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.
GeneDx	RCV000235971	SCV000293368	pathogenic	not provided	2018-10-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4999A>T at the cDNA level and p.Lys1667Ter (K1667X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also defined as BRCA1 5118A>T using alternate nomenclature, has been reported in at least one individual who had undergone testing for Hereditary Breast and Ovarian Cancer syndrome (Coulet 2000) and is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112459	SCV000326101	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774937	SCV000909000	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in at least one individual affected with recurrent ovarian cancer (doi: 10.12892/ejgo5165.2019). 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.
Ambry Genetics	RCV000774937	SCV001185248	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-07	criteria provided, single submitter	clinical testing	The p.K1667* pathogenic mutation (also known as c.4999A>T), located in coding exon 15 of the BRCA1 gene, results from an A to T substitution at nucleotide position 4999. This changes the amino acid from a lysine to a stop codon within coding exon 15. This mutation has been detected in hereditary breast/ovarian cancer families (Coulet F et al. Genet. Test Mol. Biomarkers. 2010 Oct;14(5):677-90; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). 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.
Invitae	RCV001853016	SCV002176428	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1667*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55353). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198). This variant is not present in population databases (gnomAD no frequency).
Baylor Genetics	RCV000112459	SCV004217012	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-12-22	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112459	SCV000145257	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112459	SCV001242775	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro