Submissions for variant NM_007294.4(BRCA1):c.1921dup (p.Ile641fs)

dbSNP: rs397507194

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031015	SCV000299669	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	RCV000129268	SCV000184028	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The c.1921dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1921, causing a translational frameshift with a predicted alternate stop codon (p.I641Nfs*2). This mutation has been detected in breast and/or ovarian cancer patients (Kwong A et al. J Med Genet. 2016 Jan;53(1):15-23; LaDuca H et al. PLoS One. 2017 Feb 2;12(2):e0170843; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). 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	RCV000031015	SCV000325183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000031015	SCV001424376	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Invitae	RCV001852615	SCV002127334	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile641Asnfs*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 high-risk of familial breast and/or ovarian cancer (PMID: 26187060). ClinVar contains an entry for this variant (Variation ID: 37434). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001852615	SCV004029059	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1921dupA (p.Ile641AsnfsX2) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251006 control chromosomes in gnomAD. c.1921dupA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Cheema_2020, Kwong_2015). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33083013, 26187060). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (all Pathogenic). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031015	SCV000053608	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-04-15	no assertion criteria provided	clinical testing