ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5533dup (p.Tyr1845fs)

dbSNP: rs397509294
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Total submissions: 5
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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) RCV000660965 SCV000783204 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000520200 SCV000617443 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA1 is denoted c.5533dupT at the cDNA level and p.Tyr1845LeufsX35 (Y1845LfsX35) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTC[dupT]ACCA. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 1845 in the last exon of the gene, and results in an extension of the protein. The last 19 amino acids are lost and replaced with 34 incorrect amino acids, disrupting the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). BRCA1 c.5533dupT, also reported as BRCA1 c.5533_5534insT and BRCA1 5652insT using alternate nomenclature, has been observed in at least two individuals with suspected Hereditary Breast and Ovarian Cancer (Judkins 2005, Sugano 2008). Based on the currently available information, we consider this duplication to be a pathogenic variant.
Invitae RCV001042329 SCV001206005 pathogenic Hereditary breast ovarian cancer syndrome 2022-09-06 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 55618). 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 frameshift has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 22798144). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the BRCA1 gene (p.Tyr1845Leufs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the BRCA1 protein and extend the protein by 15 additional amino acid residues.
Ambry Genetics RCV002345358 SCV002648748 pathogenic Hereditary cancer-predisposing syndrome 2023-01-30 criteria provided, single submitter clinical testing The c.5533dupT pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from a duplication of T at nucleotide position 5533, causing a translational frameshift with a predicted alternate stop codon (p.Y1845Lfs*35). This mutation has been reported in Japanese and Korean cohorts with hereditary breast and ovarian cancer (Kim H et al. Breast Cancer Res Treat 2012 Aug;134(3):1315-26; Cancer Sci 2008 Oct;99(10):1967-76). This alteration occurs at the 3' terminus of the BRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 15 amino acids. This frameshift impacts the last 19 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration was found to be non-functional in an assay of transcriptional activation (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001042329 SCV002819364 pathogenic Hereditary breast ovarian cancer syndrome 2022-12-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5533dupT (p.Tyr1845LeufsX35) causes a frameshift which disrupts the last 19 amino acids and results in an extension of the encoded protein, affecting the BRCT domain (IPR001357). The variant was absent in 250824 control chromosomes (gnomAD). It has also been reported in the literature in individuals affected with or suspected of Hereditary Breast And Ovarian Cancer Syndrome (e.g. Judkins_2005, Sugano_2008, Laitman_2019, Fostria_2020). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant, c.5558dupA (p.Tyr1853X), which similarly impacts the BRCT domain has been classified as pathogenic. Four submitters, including the expert panel ENIGMA, have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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