Submissions for variant NM_000465.4(BARD1):c.1738G>A (p.Glu580Lys)

gnomAD frequency: 0.00455  dbSNP: rs35306212

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212136	SCV000167167	benign	not specified	2013-10-23	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	RCV000129032	SCV000172941	benign	Hereditary cancer-predisposing syndrome	2014-11-26	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	RCV000205575	SCV000262042	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205575	SCV000427208	benign	Familial cancer of breast	2018-01-12	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	RCV000205575	SCV000488648	benign	Familial cancer of breast	2016-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129032	SCV000682727	benign	Hereditary cancer-predisposing syndrome	2014-11-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212136	SCV000806112	benign	not specified	2017-01-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000205575	SCV000885060	benign	Familial cancer of breast	2022-03-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757028	SCV000888800	benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225401	SCV002505103	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212136	SCV002760237	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129032	SCV002819181	benign	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000205575	SCV004016363	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205575	SCV004019244	benign	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492559	SCV004239891	benign	Breast and/or ovarian cancer	2022-09-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000757028	SCV001553406	likely benign	not provided		no assertion criteria provided	clinical testing	The BARD1 p.Glu580Lys variant was not identified in the literature nor was it identified in the Cosmic and MutDB, databases. The variant was identified in dbSNP (ID: rs35306212) as “With Likely benign allele” and in the ClinVar and Clinvitae databases as benign by GeneDx, Ambry Genetics, Invitae, Counsly, Quest diagnostics Nicholds Institue San Juan Capistrano and as likely benign by Illumina. The variant is identified 1X in the Zhejiang Colon Cancer Database databases with no further data given. The variant was also identified in the 1000 Genomes Project in 26 of 5000 chromosomes (frequency: 0.005) and in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American and in 61 of 4406 African American alleles. The variant was further identified in control databases in 475 of 277030 chromosomes (2 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 391 of 24036 chromosomes (freq: 0.02), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 58 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 10 of 126528 chromosomes (freq: 0.00008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Glu580Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign.