Submissions for variant NM_007294.4(BRCA1):c.3008_3009del (p.Asn1002_Phe1003insTer)

dbSNP: rs80357617

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)	RCV000077532	SCV000299870	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	RCV000048040	SCV000076053	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.Phe1003*) 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 (PMID: 10644434). This variant is also known as 3127del2. ClinVar contains an entry for this variant (Variation ID: 54747). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131913	SCV000186968	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	The c.3008_3009delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3008 to 3009, predicted to lead to an alternate stop codon (p.F1003*). This mutation has been identified in one family with hereditary breast and ovarian cancer (HBOC) syndrome (Wagner T et al. Genomics 1999 Dec; 62(3):369-76). This mutation has also been reported in a female with advanced breast cancer who exhibited partial response to treatment with a PARP inhibitor (Tutt A et al. Lancet 2010 Jul; 376(9737):235-44). This alteration was also identified in 1/2575 unselected patients with breast cancer and 0/2809 healthy control individuals from a Malaysian cohort and in 1/1010 Indian individuals who met clinical BRCA testing criteria (Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). In addition, this mutation was identified in a cohort of 165 formalin-fixed, paraffin-embedded non-tumor samples from deceased patients suspected to have a BCRA1/2 alteration based on BOADICEA risk estimation scores (Petersen AH et al. Eur. J. Hum. Genet., 2016 Aug;24:1104-11). Of note, this mutation is also designated as 3127delTT 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.
GeneKor MSA	RCV000239209	SCV000296794	pathogenic	not specified	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077532	SCV000325523	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000481473	SCV000566166	pathogenic	not provided	2022-10-03	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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal history of BRCA1-related cancers (Wagner et al., 1999; Singh et al., 2018; Wen et al., 2018); This variant is associated with the following publications: (PMID: 26733283, 28993434, 20609467, 10644434, 29470806)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481473	SCV000888879	pathogenic	not provided	2018-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131913	SCV001352972	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five unrelated individuals affected with breast or ovarian cancer (PMID: 20104584, 28993434, 29470806; BIC database; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 10644434, 24249303). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048040	SCV001360720	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3008_3009delTT (p.Phe1003X) 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 250840 control chromosomes (gnomAD). c.3008_3009delTT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Crawford_2017, Nakamura_2013, Singh_2018, Wen_2017). 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. Seven submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000481473	SCV001449632	pathogenic	not provided	2016-03-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077532	SCV004215112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077532	SCV000109333	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-06-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077532	SCV000144607	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	RCV000048040	SCV000587271	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077532	SCV002589100	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing