Submissions for variant NM_007294.4(BRCA1):c.69_79delGTGTCCCATCT (p.Cys24fs)

dbSNP: rs80357696

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111682	SCV000282349	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049106	SCV000077119	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys24Serfs*13) 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 cancer and ovarian cancer (PMID: 2246425, 7837387, 10498392, 20104584, 22711857, 25682074, 26543556). This variant is also known as 188del11 and 189del11. ClinVar contains an entry for this variant (Variation ID: 55676). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131391	SCV000186367	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-04	criteria provided, single submitter	clinical testing	The c.70_80del11 pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a deletion of 11 nucleotides at nucleotide positions 70 to 80, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*13). This mutation has been reported in multiple individuals with hereditary breast, ovarian, and/or pancreatic cancer (Berman DB et al. Am. J. Hum. Genet. 1996 Jun;58:1166-76; Frank TS et al. J. Clin. Oncol. 2002 Mar;20:1480-90; Kurian A et al. J. Clin. Oncol. 2008 Oct;26(29):4752-8; Shindo K et al. J. Clin. Oncol. 2017 Oct;35(30):3382-3390). Of note, this alteration is also designated as 188del11 and 189del11 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111682	SCV000326397	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486060	SCV000568440	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Frameshift 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 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 189_199del11 or c.69_79delGTGTCCCATCT; This variant is associated with the following publications: (PMID: 16267036, 7837387, 7545954, 18779604, 26543556, 8651293, 12402332, 10498392, 8533757, 28767289, 31090900, 30787465, 31464824, 25682074, 36098958, 34022715, 34887416)
Counsyl	RCV000111682	SCV000677630	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-03-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486060	SCV000887731	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast cancer, PMIDs: 22711857 (2012), 26543556 (2015), and 25682074 (2015)) and pancreatic cancer (PMID: 28767289 (2017)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049106	SCV001363982	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.70_80del11 (p.Cys24SerfsX13) 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 251038 control chromosomes.The variant, c.70_80del11, has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (eg. Berman_1996, Hopper_1999, Alsop_2012, Dean_2015, Wong-Brown_2015). 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. Nine ClinVar submissions including one expert panel (ENIGMA) have submitted 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.
Color Diagnostics, LLC DBA Color Health	RCV000131391	SCV002052187	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	This variant deletes the last 11 nucleotides in exon 2 in 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 188del11 and 189del11 in the literature. This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7837387, 8651293, 10498392, 18779604, 22711857, 25682074, 26543556) and one individual each affected with endometrial (PMID: 8651293) and pancreatic cancer (PMID: 28767289). This variant has been identified in 21 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.
Genetic Services Laboratory, University of Chicago	RCV000486060	SCV002065918	pathogenic	not provided	2022-01-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a 11 base pair deletion in exon 2, c.70_80del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 12 amino acids downstream of the change, p.Cys24Serfs*13. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. The c.70_80del sequence change has not been described in the population databases such as ExAC and gnomAD (dbSNP rs1220450191). This pathogenic sequence change has previously been described in an individual with breast cancer and ovarian cancer (PMID: 7837387, 10498392, 25682074, 22711857, 26543556).
All of Us Research Program, National Institutes of Health	RCV000111682	SCV004823701	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-27	criteria provided, single submitter	clinical testing	This variant deletes the last 11 nucleotides in exon 2 in 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 188del11 and 189del11 in the literature. This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7837387, 8651293, 10498392, 18779604, 22711857, 25682074, 26543556) and one individual each affected with endometrial (PMID: 8651293) and pancreatic cancer (PMID: 28767289). This variant has been identified in 21 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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	RCV000111682	SCV005058214	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-29	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111682	SCV000144182	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	RCV000049106	SCV000587007	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research