Submissions for variant NM_007294.4(BRCA1):c.5445G>A (p.Trp1815Ter)

dbSNP: rs397509284

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077624	SCV000300260	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	RCV000166210	SCV000216989	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.W1815* pathogenic mutation (also known as c.5445G>A), located in coding exon 21 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5445. This changes the amino acid from a tryptophan to a stop codon within coding exon 21. This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 49 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). This mutation has been detected in numerous breast/ovarian cancer patients and is recurrent in high-risk Korean cohorts (Seo JH et al. Hum. Mutat. 2004 Oct;24(4):350; Jang JH et al. J. Hum. Genet. 2012 Mar;57(3):212-5; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151(1):157-68; Maxwell KN et al. Nat Commun, 2017 08;8:319; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077624	SCV000326314	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077624	SCV000786437	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166210	SCV001352264	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 22 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496513	SCV001582011	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1815*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the BRCA1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15365993, 28205045, 28724667, 28831036, 29446198). This variant is also known as 5564G>A. ClinVar contains an entry for this variant (Variation ID: 55581). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 12400015, 21922593). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000077624	SCV004045510	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Sharing Clinical Reports Project (SCRP)	RCV000077624	SCV000109427	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-15	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496513	SCV000587510	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077624	SCV001243340	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Laboratory for Genotyping Development, RIKEN	RCV003162420	SCV002758502	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research