Submissions for variant NM_007294.4(BRCA1):c.5068A>T (p.Lys1690Ter)

dbSNP: rs397507239

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031207	SCV000300194	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031207	SCV000326129	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031207	SCV000785794	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-28	criteria provided, single submitter	clinical testing
Invitae	RCV001384446	SCV001583944	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 37626). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22333603, 29446198, 29470806). This variant is present in population databases (rs397507239, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys1690*) 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).
Sema4, Sema4	RCV002257366	SCV002537806	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
Ambry Genetics	RCV002257366	SCV002644083	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	The p.K1690* pathogenic mutation (also known as c.5068A>T), located in coding exon 15 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5068. This changes the amino acid from a lysine to a stop codon within coding exon 15. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620) and has been reported in the literature in a patient diagnosed with triple negative breast cancer (Robertson L. Br J Cancer. 2012 Mar;106(6):1234-8). 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	RCV001529865	SCV003936624	pathogenic	not provided	2022-12-28	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; Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); Identified in patients with breast, ovarian, pancreatic, or prostate cancer (Robertson et al., 2012; Singh et al., 2018; Mehta et al., 2022); 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 5187A>T; This variant is associated with the following publications: (PMID: 29446198, 22333603, 26023681, 20104584, 30209399, 29470806, 35698740, 29922827)
Baylor Genetics	RCV000031207	SCV004215046	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031207	SCV000053807	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-05-12	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031207	SCV001242039	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529865	SCV001744066	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529865	SCV001958216	pathogenic	not provided		no assertion criteria provided	clinical testing