Submissions for variant NM_007294.4(BRCA1):c.5511G>A (p.Trp1837Ter)

dbSNP: rs80356914

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112692	SCV000300274	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	RCV000112692	SCV000326349	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112692	SCV000564308	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000496465	SCV003441893	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1837*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the BRCA1 protein. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26951538). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 21922593; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 55609).
Ambry Genetics	RCV003362682	SCV004057367	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The p.W1837* pathogenic mutation (also known as c.5511G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5511. This changes the amino acid from a tryptophan to a stop codon within coding exon 22. This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 27 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112692	SCV000145561	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496465	SCV000587518	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112692	SCV001244040	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
CZECANCA consortium	RCV001270978	SCV001451784	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112692	SCV004243904	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing