ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1448A>G (p.His483Arg) (rs587781874)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130200 SCV000185037 likely benign Hereditary cancer-predisposing syndrome 2020-05-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000206542 SCV000259924 uncertain significance Familial cancer of breast 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 483 of the BARD1 protein (p.His483Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs587781874, ExAC 0.003%). This variant has not been reported in the literature in individuals with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141608). This variant has been reported not to substantially affect BARD1 protein function (PMID: 30925164). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000282507 SCV000427214 uncertain significance Breast neoplasm 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000206542 SCV000785444 uncertain significance Familial cancer of breast 2017-08-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000130200 SCV000821888 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130200 SCV000903009 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284525 SCV001470360 uncertain significance not provided 2019-11-13 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354083 SCV001548611 uncertain significance Familial pancreatic carcinoma no assertion criteria provided clinical testing The BARD1 p.His483Arg variant was not identified in 6472 proband chromosomes from individuals or families with ovarian cancer, but was present in 1 of 6862 control chromosomes (frequency: 0.0002) from healthy individuals (Ramus 2015). The variant was also identified in dbSNP (ID: rs587781874) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl and two other submitters). The variant was identified in control databases in 4 of 246094 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5470 chromosomes (freq: 0.0002), Latino in 1 of 33534 chromosomes (freq: 0.00003), European in 2 of 111620 chromosomes (freq: 0.00002), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His483 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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