Submissions for variant NM_007294.4(BRCA1):c.182G>A (p.Cys61Tyr)

dbSNP: rs80357093

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235674	SCV000293061	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: impaired BARD1 binding and E3-auto-ubiquitination activity, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Starita et al., 2015; Findlay et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 301G>A; This variant is associated with the following publications: (PMID: 15235020, 20215423, 28664506, 26287763, 23867111, 23161852, 18159056, 22752604, 29446198, 25428789, 32741062, 33087888, 8944023, 24389207, 20104584, 30209399, 25823446)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077497	SCV000325156	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775191	SCV000909417	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 61 of the BRCA1 protein. The impacted reference cysteine is one of the eight conserved cysteine/histidine for the zinc finger motif in the RING domain (PMID: 11526114). Computational prediction 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 ubiquitin E3 ligase, BARD1 binding and haploid human cell proliferation assays (PMID: 25823446, 30209399). This variant has been reported in at least seven individuals affected with breast cancer (PMID: 18159056, 22752604, 25428789, 26287763, 28664506). 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.
Ambry Genetics	RCV000775191	SCV001173919	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.C61Y pathogenic mutation (also known as c.182G>A), located in coding exon 3 of the BRCA1 gene, results from a G to A substitution at nucleotide position 182. The cysteine at codon 61 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9; Pal T et al. Cancer. 2015 Dec;121(23):4173-80; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165:687-697). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In one high throughput functional study, this variant was shown to impair both BARD1 binding activity and E3 Ubiquitin ligase function of the protein (Starita LM et al. Genetics. 2015 Jun;200:413-22). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Based on internal structural assessment, this alteration disrupts one of the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496241	SCV001554585	pathogenic	Hereditary breast ovarian cancer syndrome	2021-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.182G>A (p.Cys61Tyr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.182G>A has been reported in the literature in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in loss of homology directed repair (HDR) activity. Three clinical diagnostic laboratories, one research submitter, and one consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496241	SCV001589380	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 61 of the BRCA1 protein (p.Cys61Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18159056, 22752604, 25428789, 26287763, 28664506). ClinVar contains an entry for this variant (Variation ID: 54364). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 22843421, 25823446, 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Cys61 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7894493, 9525870, 11278247, 19594371, 19770520, 22172724). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000077497	SCV004211768	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-03-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077497	SCV000109296	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-05-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077497	SCV000144576	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496241	SCV000587025	pathogenic	Hereditary breast ovarian cancer syndrome	2015-12-17	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000235674	SCV000591247	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Cys61Tyr variant was identified in dbSNP (ID: rs80357093) “With pathogenic allele”, HGMD, and the BIC database (6X with unknown clinical importance). The p.Cys61 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys61Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Abkevich (2004) notes that p.Cys61 is a C3HC4 RING finger canonical residue, and that the p.Cys61Tyr variant is classified as deleterious by Myriad. In addition, another variant at this amino acid position, p.Cys61Gly, has been listed in public databases as a pathogenic variant, including 45X in UMD (as a "causal" variant) and 239X in the BIC database (as a variant with clinical importance). This p.Cys61Gly variant has also been characterized as deleterious by different functional assays, including evaluations of the p.Cys61Gly variant on double strand break repair and protein expression (Li 2010, Towler 2013, Bouwman 2013), suggesting that this residue is functionally important and the p.Cys61Tyr variant may also impact protein function. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Brotman Baty Institute, University of Washington	RCV000077497	SCV001242517	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro