ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1972C>T (p.Arg658Cys) (rs3738888)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212141 SCV000167168 benign not specified 2013-10-14 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 RCV000130975 SCV000185890 benign Hereditary cancer-predisposing syndrome 2014-06-26 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 RCV000205691 SCV000262412 benign Familial cancer of breast 2020-12-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130975 SCV000292114 benign Hereditary cancer-predisposing syndrome 2014-11-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000205691 SCV000427205 likely benign Familial cancer of breast 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl RCV000205691 SCV000488548 likely benign Familial cancer of breast 2016-06-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212141 SCV000600186 likely benign not specified 2017-02-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212141 SCV000806114 benign not specified 2016-11-22 criteria provided, single submitter clinical testing
Mendelics RCV000205691 SCV000837948 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759471 SCV000888805 benign not provided 2017-08-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000759471 SCV001153288 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000205691 SCV001156753 benign Familial cancer of breast 2020-08-20 criteria provided, single submitter clinical testing
Lab. Molecular Oncology,VUB, Free University of Brussels RCV000678226 SCV000804245 uncertain significance Triple-Negative Breast Cancer Finding 2015-02-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355246 SCV001550074 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Arg658Cys variant was identified in 9 of 2368 proband chromosomes (frequency: 0.004) from individuals or families with breast and/or ovarian cancer (Karppinen 2004, Klonowska 2015, Vahteristo 2006). The variant was also identified in the following databases: dbSNP (ID: rs3738888) as “With other allele”, ClinVar (6x, as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics.Inc, and as likely benign by Illumina Clinical Services, Counsyl), Clinvitae (4x, as benign and likely benign), and Zhejiang Colon Cancer Database (6x, as probably pathogenic). The variant was not identified in Cosmic nor MutDB databases. The variant was identified in control databases in 2270 (11 homozygous) of 277098 chromosomes at a frequency of 0.008 in the following populations: Finnish in 336 of 25784 chromosomes (freq. 0.013), Latino in 425 of 34414 chromosomes (freq. 0.012), East Asian in 206 of 18868 chromosomes (freq. 0.01), European in 1067 of 126610 chromosomes (freq. 0.0084), other in 53 of 6462 chromosomes (freq. 0.008), South Asian in 125 of 30782 chromosomes (freq. 0.004), and African in 58 of 2403 chromosomes (freq. 0.0024), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg658Cys residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. There are conflicting predictions in the literature regarding the clinical significance of the p.Arg658Cys variant. Some studies refer to this variant as potentially pathological (Klonowska 2015), but functional studies do not predict clinical significance for this variant although it is in a functional domain (Lee 2015). In another study this variant has been utilized as putative benign polymorphism in multiple functional assays (Sauer 2005). A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) was identified in 1 individual with breast cancer by our laboratory, increasing the likelihood that p.Arg658Cys variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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