Submissions for variant NM_007294.4(BRCA1):c.5319dup (p.Asn1774fs)

dbSNP: rs80357823

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000074358	SCV000300238	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048927	SCV000076940	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1774Glnfs*56) 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 breast and/or ovarian cancer and pancreatic cancer (PMID: 7894491, 11938448, 18779604, 25940717, 27062684). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5319_5320insC or c.5438insC. ClinVar contains an entry for this variant (Variation ID: 55523). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131363	SCV000186339	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-20	criteria provided, single submitter	clinical testing	The c.5319dupC pathogenic mutation, located in coding exon 19 of the BRCA1 gene, results from a duplication of C at nucleotide position 5319, causing a translational frameshift with a predicted alternate stop codon (p.N1774Qfs*56). This mutation has been reported in numerous breast and/or ovarian cancer families (Castilla LH et al. Nat. Genet. 1994 Dec;8:387-91; Nedelcu R et al. Eur. J. Hum. Genet. 2002 Feb;10:150-2; Judkins T et al. Cancer Res. 2005 Nov;65:10096-103; Brooks GA et al. Cancer Biol. Ther. 2006 Sep;5:1098-102; Kurian AW et al. J. Clin. Oncol. 2008 Oct;26:4752-8; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). This mutation was also reported in an individual with pancreatic cancer who met NCCN BRCA1 and BRCA2 testing criteria (Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9). Of note, this alteration is also designated as 5438insC and 5319_5320insC 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. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478417	SCV000296278	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	The BRCA1 c.5319dup (p.Asn1774Glnfs*56) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 11938448 (2002), 16267036 (2005), 18779604 (2008), 27062684 (2016), 30103829 (2018), and 32438681 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000074358	SCV000326261	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478417	SCV000564751	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; 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 5438dupC; This variant is associated with the following publications: (PMID: 28888541, 31794323, 32438681, 7894491, 11938448, 20104584, 27062684, 18779604, 16267036, 16931905, 26295337, 30103829, 25940717, 30787465)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000048927	SCV000591611	pathogenic	Hereditary breast ovarian cancer syndrome	2014-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048927	SCV001363932	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5319dupC (p.Asn1774GlnfsX56) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251376 control chromosomes. c.5319dupC has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Castilla_1994, Judkins_2005, Holter_2015, Azzollini_2016, Cardoso_2018). 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. Five submitters including an expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000478417	SCV001715191	pathogenic	not provided	2020-11-30	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Color Diagnostics, LLC DBA Color Health	RCV000131363	SCV001734764	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 20 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.5319_5320insC and 5438insC in the literature. This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID: 7894491, 16912212, 18779604, 27062684, 30103829) and pancreatic cancer (PMID: 25940717). 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.
Baylor Genetics	RCV000074358	SCV004215044	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804021	SCV005425637	pathogenic	BRCA1-related cancer predisposition	2024-09-02	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 20 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.5319_5320insC and 5438insC in the literature. This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID: 7894491, 16912212, 18779604, 27062684, 30103829) and pancreatic cancer (PMID: 25940717). 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.
OMIM	RCV000074358	SCV000039538	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000074358	SCV000053839	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-11-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000074358	SCV000145451	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	RCV000048927	SCV000587492	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735454	SCV000863591	pathogenic	Breast and/or ovarian cancer	2009-09-04	no assertion criteria provided	clinical testing