Submissions for variant NM_000465.4(BARD1):c.609A>C (p.Gly203=)

gnomAD frequency: 0.00787  dbSNP: rs28997574

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212118	SCV000167163	benign	not specified	2013-10-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000128964	SCV000172846	benign	Hereditary cancer-predisposing syndrome	2014-11-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000227089	SCV000284970	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000227089	SCV000427219	benign	Familial cancer of breast	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000227089	SCV000488567	benign	Familial cancer of breast	2016-06-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128964	SCV000537362	benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212118	SCV000806131	benign	not specified	2016-11-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477528	SCV000887598	benign	not provided	2022-06-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000227089	SCV001477708	benign	Familial cancer of breast	2023-11-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212118	SCV002067945	benign	not specified	2020-09-18	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225400	SCV002505133	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128964	SCV002529630	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212118	SCV002760253	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000227089	SCV004016360	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000227089	SCV004019261	benign	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354550	SCV001549195	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Gly203= variant was identified in 8 of 856 proband chromosomes (frequency: 0.009) from Belgian, Polish and Finnish individuals or families with high risk BRCA1/2 negative breast and/or ovarian cancer and was present in 2 of 140 control chromosomes (frequency: 0.01) from healthy individuals (De Brakeleer 2010, Ratajska 2012 , Karppinen 2004). The variant was also identified in dbSBP (ID: rs28997574) “With Likely benign allele”, ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics Inc, and likely benign by Illumina), and the Zhejiang Colon Cancer Database (3x); but was not identified in MutDB and Cosmic. The variant was identified in control databases in 2280 (23 homozygous) of 259884 chromosomes at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 270 of 9086 chromosomes (freq: 0.03), Other in 110 of 6022 chromosomes (freq: 0.02), Latino in 410 of 30290 chromosomes (freq: 0.014). The p.Gly203Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.