ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5558A>G (p.Tyr1853Cys) (rs80357258)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563885 SCV000665902 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-08 criteria provided, single submitter clinical testing The p.Y1853C variant (also known as c.5558A>G), located in coding exon 22 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5558. The tyrosine at codon 1853 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in Japanese patients with personal and/or family histories of breast and/or ovarian cancer (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Kawaku S et al. J. Hum. Genet. 2013 Sep;58:618-21; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8). Structural and functional analyses have suggested that this variant, which is located in the BRCT domain, affects folding, binding, transcription, and stability of the protein (Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Williams RS et al. Nat. Struct. Mol. Biol. 2004 Jun;11:519-25; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem. 2010 Jun;285:20080-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, several evolutionary and structurally based in silico models predict that this alteration is either likely to be deleterious or deleterious (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3:e26). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000757927 SCV000886445 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-03 criteria provided, single submitter research The BRCA1 variant designated as p.Y1853C (NM_007294.3:c.5558A>G, historically referred to as 5677A>G) was previously classified as a variant of uncertain significance and is now classified as likely pathogenic. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303). Analysis of this family shows yields a likelihood ratio of 1.9 to 1 (Thompson, et al., 2003, PMID:290079) that this allele is causing cancer within the family. This BRCA1 amino acid position is highly conserved. The variant is not listed in population databases such as ExAC or gnomAD. Functional data suggests that this variant compromises the BRCT domain (Lee 2010, PMID:20516115). More recent functional data is consistent with earlier findings and also indicates that the variant leads to a non-functional protein (Findlay et al, 2018, PMID:30209399). The combined results are consistent with a classification of likely pathogenic. This variant is predicted to alter BRCA1 function and increase breast and ovarian cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Health, Inc RCV000563885 SCV000908975 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000757927 SCV001362761 pathogenic Hereditary breast and ovarian cancer syndrome 2019-09-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5558A>G (p.Tyr1853Cys) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250374 control chromosomes. c.5558A>G has been reported in the literature from Japan, India and Brazil in individuals affected with Hereditary Breast and Ovarian Cancer (Sugano_2008, Nakamura_2015, Kawaku_2013, Arai_2018, Singh_2018, Cotrim_2019, Tsai_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (Lee_2010, Kawaku_2013, Woods_2016). The most pronounced variant effect results in a reduction of activity across multiple independent measures ranging from transcriptional assays (<10% of WT), structural stability (32% of WT), phosphopeptide binding activity (14% of WT), and protease sensitivity (30% of WT). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the overall directionality of evidence spanning over a decade supporting a pathogenic outcome as evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000757927 SCV001576981 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-10 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1853 of the BRCA1 protein (p.Tyr1853Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with breast cancer in a family (PMID: 23842040). It has also been observed in several individuals with hereditary breast and/or ovarian cancer (PMID: 29470806, 29176636, 30287823, 30374176). ClinVar contains an entry for this variant (Variation ID: 55627). This variant has been reported to affect BRCA1 protein function (PMID: 23842040, 20516115, 20378548, 14534301,30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112703 SCV000145576 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112703 SCV001237705 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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