Submissions for variant NM_007294.4(BRCA1):c.4396dup (p.Ser1466fs)

dbSNP: rs397509170

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587752	SCV000699142	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-10	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4396dupA (p.Ser1466Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.4401delG, p.Asn1468fs). Mutation taster predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121378 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001189444	SCV001356737	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-06	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 13 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002476277	SCV002009441	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002476277	SCV002774263	likely pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	The BRCA1 c.4396dup (p.Ser1466Lysfs*10) variant alters the translational reading frame of the BRCA1 mRNA and is predicted to cause the premature termination of BRCA1 protein synthesis. The variant has not been reported in individuals with BRCA1-related diseases in the published literature. 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 likely pathogenic.
Invitae	RCV000587752	SCV004376084	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1466Lysfs*10) 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 variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496380). 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.