Submissions for variant NM_007294.4(BRCA1):c.5306A>G (p.Tyr1769Cys)

dbSNP: rs397509257

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048917	SCV000076930	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000166677	SCV000217485	likely benign	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000409270	SCV000488527	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000657045	SCV000567504	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer, but also in unaffected controls (Akbari et al., 2011; Juwle et al., 2012; Tung et al., 2015; Momozawa et al., 2018; Singh et al., 2018; Kim et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5425A>G; This variant is associated with the following publications: (PMID: 24728327, 21965345, 24362935, 22752604, 30209399, 30287823, 29470806, 30725392, 31907386, 34063308, 32803532, 25186627, 25348405, 32812259)
Color Diagnostics, LLC DBA Color Health	RCV000166677	SCV000910943	likely benign	Hereditary cancer-predisposing syndrome	2016-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657045	SCV001133623	likely benign	not provided	2023-08-31	criteria provided, single submitter	clinical testing
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV000048917	SCV001430324	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657045	SCV002009423	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120264	SCV002051210	uncertain significance	not specified	2021-12-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5306A>G (p.Tyr1769Cys) results in a non-conservative amino acid change located in the 2nd BRCT domain, which functions as a protein-protein interaction module (IPR001357). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-05 in 252816 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is somewhat lower than the maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.001), allowing no conclusion about variant significance. The variant, c.5306A>G, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Akbari_2011, Juwle_2012, So_2019, Kim_2020), however, it was also found in healthy controls (Juwle_2012, Bodian_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.3455T>G (p.Leu1152X), in an internal LCA sample; BRCA2 c.2983G>T (p.Gly995X), Kim_2020), providing supporting evidence for a benign role. At least one functional study reports experimental evidence evaluating an impact on protein function and showed an intermediate effect of this variant on homology directed repair (HDR) activity (Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=7), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000409270	SCV004047406	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant c.5306A>G (p.Tyr1769Cys) in BRCA1 gene has been reported in individuals affected with breast and/or ovarian cancer, as wells as in healthy control individuals(Juwle A et.al.,2012). This variant has been reported to the ClinVar database as Uncertain Significance. The p.Tyr1769Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00005968% is reported in gnomAD. The amino acid Tyr at position 1769 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr1769Cys in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657045	SCV004224359	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492393	SCV004240281	uncertain significance	Breast and/or ovarian cancer	2022-11-23	criteria provided, single submitter	clinical testing
ITMI	RCV000120264	SCV000084416	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353476	SCV000591609	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Tyr1769Cys variant was identified in 1 of 2690 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer and was present in 1 of 1362 control chromosomes (frequency: 0.001) from healthy individuals (Akbari 2011, Bodian 2014). The low number of observations of this variant is not substantive enough to draw a conclusion about clinical signifcance. The variant was not identified in GeneInsight, HGMD, UMD, COSMIC, BIC, Google or LOVD database searches. The variant was identified in the ClinVar database 2X with the clinical significance not provided. The p.Tyr1769 residue is not conserved in mammals and the variant amino acid Cysteine (Cys) is present in the mouse and chicken increasing the likelihood that this variant does not have clinical significance. Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, although this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, althouch we lean towards a more benign role for this variant. This variant is classified as predicted benign.
Brotman Baty Institute, University of Washington	RCV000409270	SCV001238498	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro