ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs80357629
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Total submissions: 16
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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 variantquestions@myriad.com.
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

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