Submissions for variant NM_007294.4(BRCA1):c.1016del (p.Lys339fs)

dbSNP: rs80357569

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)	RCV000030967	SCV000299521	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000030967	SCV000195887	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222143	SCV000278698	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The c.1016delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1016, causing a translational frameshift with a predicted alternate stop codon (p.K339Rfs*2). This alteration, also described as 1135delA and 1129delA, has been detected in multiple, ethnically diverse breast and/or ovarian cancer patients/ families (Hogervorst FB et al. Nat. Genet. 1995 Jun;10(2):208-12; Janatová M et al. Neoplasma 2003; 50(4):246-50; Pohlreich P et al. Med Princ Pract; 2003;12(1):23-9; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488; Concolino P et al. Int J Mol Sci. 2019 Jul;20:; Laitman Y et al. Hum Mutat. 2019 11;40:e1-e23; Shao D et al. Cancer Sci. 2020 Feb;111:647-657). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030967	SCV000324929	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507496	SCV000600235	pathogenic	not provided	2024-07-11	criteria provided, single submitter	clinical testing	The BRCA1 c.1016del (p.Lys339Argfs*2) 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 individuals with breast and/or ovarian cancer (PMIDs: 16168118 (2005), 16287141 (2005), 16683254 (2006), 19353265 (2009), 27836010 (2016), 31336956 (2019), 31742824 (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.
GeneDx	RCV000507496	SCV000778879	pathogenic	not provided	2018-07-27	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.1016delA at the cDNA level and p.Lys339ArgfsX2 (K339RfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAAAA[delA]GGTA. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 339, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1016delA, previously published as 1129delA and 1135delA using alternate nomenclature, has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (Hagervorst 1995, Polreich 2003, Kwong 2009, Fang 2014, Rebbeck 2016). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496871	SCV001364036	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1016delA (p.Lys339ArgfsX2) 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. The variant was absent in 251174 control chromosomes (gnomAD). c.1016delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rebbeck_2018, Laitman_2019). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters including one expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496871	SCV001586457	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys339Argfs*2) 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 (PMID: 7663517, 15024741, 16287141, 16683254, 22970155, 27157322, 27836010). This variant is also known as 1129delA and 1135delA. ClinVar contains an entry for this variant (Variation ID: 37386). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000222143	SCV001735006	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-23	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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 has been reported in individuals affected with breast and/or ovarian cancer (PMID: 7663517, 9150151, 10874312, 11463009, 16168118, 19353265, 22970155). 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	RCV000030967	SCV004216915	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-09-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000030967	SCV000053558	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-05-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030967	SCV000143983	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496871	SCV000587093	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000030967	SCV000733663	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001270960	SCV001451764	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357938	SCV001553548	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000507496	SCV001905740	pathogenic	not provided		no assertion criteria provided	clinical testing