Submissions for variant NM_007294.4(BRCA1):c.5352dup (p.Gln1785fs)

dbSNP: rs80357744

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112628	SCV000300247	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112628	SCV000326288	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496764	SCV002157235	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1785Thrfs*45) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the BRCA1 protein. 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: 125832). This variant disrupts the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect on BRCA1 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr1853*) that lies downstream of this variant has been determined to be pathogenic (PMID: 21922593, 10811118, 11739404, 12400015, 7894493, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002345407	SCV002641528	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-18	criteria provided, single submitter	clinical testing	The c.5352dupA variant, located in coding exon 20 of the BRCA1 gene, results from a duplication of A at nucleotide position 5352, causing a translational frameshift with a predicted alternate stop codon (p.Q1785Tfs*45). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of BRCA1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 35 amino acids of the protein. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112628	SCV000145477	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496764	SCV000587502	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research