Submissions for variant NM_007294.4(BRCA1):c.3243_3288dup (p.Ser1097delinsCysTyrAlaTer)

dbSNP: rs1555588016

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256950	SCV000323578	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000256950	SCV000325584	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002227114	SCV002009453	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859508	SCV002227766	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 266346). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser1097Cysfs*4) 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002227114	SCV002506191	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing	The BRCA1 c.3243_3288dup; p.Ser1097fs variant (rs1555588016), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 266346) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting 46 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/
MGZ Medical Genetics Center	RCV000256950	SCV002581909	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-03-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493557	SCV004244355	pathogenic	Familial cancer of breast	2024-10-04	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001859508	SCV005848160	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-10	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PVS1 (very strong pathogenic): table 4, PM5 (strong pathogenic): Table 4, PTC in Exon 11