ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1738G>A (p.Glu580Lys) (rs35306212)

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Total submissions: 11
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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 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212136 SCV000600183 benign not specified 2016-09-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129032 SCV000682727 benign Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212136 SCV000806112 benign not specified 2017-01-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757028 SCV000885060 likely benign not provided 2017-06-27 criteria provided, single submitter clinical testing The BARD1 c.1738G>A;p.Glu580Lys variant has not been published in the medical literature, but is listed in the ClinVar database ( Variation ID: 136499). The variant is listed in the dbSNP variant database (rs35306212) with an allele frequency of 1.3845 percent (61/4345 alleles) in African Americans in the Exome Variant Server and 1.627 percent (391/24036 alleles, 1 homozygote) in the African population in the Genome Aggregation Database. The amino acid at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Considering available information, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000757028 SCV000888800 benign not provided 2016-09-27 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.

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