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

dbSNP: rs80357258

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563885	SCV000665902	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	clinical testing	The p.Y1853C pathogenic mutation (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 patients with personal and/or family histories of breast and/or ovarian cancer, including many of Japanese and Indian descent (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; Kobayashi Y et al. Jpn J Clin Oncol, 2021 Feb;51:213-217; Tokunaga H et al. PLoS One, 2021 Jan;16:e0236907; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This alteration segregates with disease in multiple families (Kawaku S et al. J Hum Genet, 2013 Sep;58:618-21; Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This alteration is non-functional in multiple different assays including a haploid cell survival assay, multiple protease/protein stabilization assays, peptide binding and specificity assays and transcription activation assays (Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem. 2010 Jun;285:20080-7; Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000757927	SCV000886445	likely pathogenic	Hereditary breast 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 analyze.myvariant.org (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 Diagnostics, LLC DBA Color Health	RCV000563885	SCV000908975	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1853 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399) and in transcription activation, phosphopeptide binding and protein stability (PMID: 20516115, 23842040). This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 19016756, 23842040, 24249303, 30606148, 30287823; Color internal data). This variant has been reported to segregate with breast cancer in at least one family (PMID: 23842040), and a multifactorial analysis has reported segregation and family history likelihood ratios for pathogenicity of 12.663 and 2.2927, respectively (PMID: 31131967). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000757927	SCV001362761	pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-31	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 (examples, 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 (examples, Lee_2010, Kawaku_2013, Woods_2016, Findlay_2018). 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) and loss of homology directed repair (HDR) activity (Findlay_2018). Four 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	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-09	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1853 of the BRCA1 protein (p.Tyr1853Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 20378548, 20516115, 23842040, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55627). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer and breast cancer (PMID: 23842040, 29176636, 29470806, 30287823, 30374176). It has also been observed to segregate with disease in related individuals.
GeneDx	RCV002285262	SCV002575469	likely pathogenic	not provided	2022-03-21	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Sugano 2008, Kawaku 2013, Nakamura 2015, Arai 2018, Momozawa 2018, Singh 2018, Cotrim 2019, Tsai 2019); Published functional studies demonstrate a damaging effect: impaired protein stability, binding, sensitivity, transciptional activity, and cell survival (Williams 2004, Lee 2010, Rowling 2010, Kawaku 2013, Woods 2016, Findlay 2018, Fernandes 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5677G>A; This variant is associated with the following publications: (PMID: 15235020, 23842040, 30765603, 20516115, 28781887, 31131967, 20378548, 15133503, 14534301, 30209399, 29470806, 30606148, 30374176, 30287823, 29176636, 24249303, 19016756, 17305420)
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112703	SCV000145576	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112703	SCV001237705	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Laboratory for Genotyping Development, RIKEN	RCV003162422	SCV002758500	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000112703	SCV004243900	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing