Submissions for variant NM_007294.4(BRCA1):c.5179A>T (p.Lys1727Ter)

dbSNP: rs80357347

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031226	SCV000300219	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	RCV000048844	SCV000076857	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1727*) 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 hereditary breast cancer (PMID: 7493024, 16287141). It has also been observed to segregate with disease in related individuals. This variant is also known as 5298A>T. ClinVar contains an entry for this variant (Variation ID: 37645). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131827	SCV000186882	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-10	criteria provided, single submitter	clinical testing	The p.K1727* pathogenic mutation (also known as c.5179A>T), located in coding exon 17 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5179. This changes the amino acid from a lysine to a stop codon within coding exon 17. This pathogenic mutation has been reported in multiple individuals or families with ovarian and/or breast cancer, as well as in one individual diagnosed with uterine cancer (Gayther SA et al. Nat. Genet., 1995 Dec;11:428-33; Spitzer E et al. Int. J. Cancer, 2000 Feb;85:474-81; Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Kroiss R et al. Hum Mutat, 2005 Dec;26:583-9; Walker LC et al. Eur J Hum Genet, 2017 04;25:432-438; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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). Of note, this alteration is also designated as 5298A>T 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031226	SCV000267718	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000237069	SCV000292860	pathogenic	not provided	2023-06-12	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 (gnomAD); Observed in association with BRCA1-related cancers (Gayther et al., 1995; Spitzer et al., 2000; Kroiss et al., 2005; Hahnen et al., 2017; Evans et al., 2022); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5298A>T; This variant is associated with the following publications: (PMID: 11802209, 29446198, 27756336, 10699917, 7493024, 16287141, 28715532, 27150160, 30787465, 30209399, 33758026)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031226	SCV000326195	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031226	SCV000489674	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-11-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000237069	SCV001715193	pathogenic	not provided	2020-12-07	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Sema4, Sema4	RCV000131827	SCV002537821	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000237069	SCV002774315	pathogenic	not provided	2021-08-27	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, the variant has been reported in multiple individuals and families with hereditary breast and/or ovarian cancer (PMID: 29446198 (2018), 16287141 (2005), 11802209 (2002), 10699917 (2000), 7493024 (1995)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000237069	SCV003818038	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031226	SCV000053826	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031226	SCV000145374	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048844	SCV000587474	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000031226	SCV001241826	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro