Submissions for variant NM_007294.4(BRCA1):c.68_69dup (p.Cys24fs)

gnomAD frequency: 0.00003  dbSNP: rs80357914

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000143834	SCV000299398	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.
Ambry Genetics	RCV000223371	SCV000273758	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657219	SCV000296302	pathogenic	not provided	2019-07-30	criteria provided, single submitter	clinical testing	The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26543556 (2015), and 30262796 (2018)). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV000657219	SCV000778945	pathogenic	not provided	2017-02-10	criteria provided, single submitter	clinical testing	This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 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.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779878	SCV000916757	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) 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 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an 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	RCV000779878	SCV001584844	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) 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 contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504947	SCV002813509	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000143834	SCV004215148	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-17	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000143834	SCV000115151	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-01-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000143834	SCV000144175	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing