Submissions for variant NM_007294.4(BRCA1):c.5558dup (p.Tyr1853Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357629

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000074357	SCV000300281	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049050	SCV000077063	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1853*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 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: 7894493, 20104584, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as (c.5677insA, Y1853_L1854delinsX). ClinVar contains an entry for this variant (Variation ID: 55628). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 10811118, 11739404, 12400015, 21922593). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000163976	SCV000214576	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-10	criteria provided, single submitter	clinical testing	The c.5558dupA pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from a duplication of A at nucleotide position 5558, causing a translational frameshift with a predicted alternate stop codon (p.Y1853*). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 11 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 identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Friedman et al. Nat. Genet. 1994 Dec;8(4):399-404; Borg et al. Hum. Mutat. 2010 Mar;31(3):E1200-40; Song H et al. Hum. Mol. Genet. 2014 Sep;23(17):4703-9; Tung N et al. Cancer, 2015 Jan;121:25-33), and has been shown to cause loss of function in functional assays (Hayes et al. Cancer Res. 2000 May;60(9):2411-8). Of note, this alteration is also designated as 5677insA in published literature. 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.
GeneDx	RCV000265181	SCV000329130	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5677dupA; This variant is associated with the following publications: (PMID: 21922593, 20104584, 7894493, 8942979, 14534301, 7795652, 27802165, 10811118, 12400015, 28392550, 25186627, 24728189, 18992264, 31013702, 24504028, 30787465, 30765603, 34439109, Levine[case report], 32322110, 33237286)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000265181	SCV000888951	pathogenic	not provided	2024-07-02	criteria provided, single submitter	clinical testing	The BRCA1 c.5558dup (p.Tyr1853*) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 7894493 (1994), 25186627 (2015), 20104584 (2010)), ovarian cancer (PMID: 24504028 (2014)), and pancreatic cancer (PMID: 32073954 (2020)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 10811118 (2000), 11739404 (2001), 12400015 (2002), 21922593 (2011)). 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 pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000163976	SCV000904687	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000265181	SCV001449857	pathogenic	not provided	2016-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049050	SCV001572495	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5558dupA (p.Tyr1853X) results in a premature termination codon, predicted to cause a truncation of the encoded protein The variant was absent in 253430 control chromosomes (gnomAD). c.5558dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Song_2014, Judkins_2005) and also has been found to co-segregate within a large affected family (Friedman_1994). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant has been found to reduce transcriptional activity (Carvalho_2007). Eight ClinVar submitters (evaluation after 2014) including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000265181	SCV003809834	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000074357	SCV004216850	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-01-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000265181	SCV005413221	pathogenic	not provided	2023-07-31	criteria provided, single submitter	clinical testing	PP4, PP5, PM2_moderate, PS4_moderate, PVS1_strong
OMIM	RCV000074357	SCV000039536	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000074357	SCV000053867	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000074357	SCV000145577	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Counsyl	RCV000074357	SCV000488476	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-07	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000049050	SCV000587522	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research