ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2282G>A (p.Ser761Asn) (rs142155101)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588281 SCV000149540 benign not provided 2018-03-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26787654, 26976419, 11807980, 28335968, 25980754, 18089818, 23056176, 17972171, 25288723, 17848578, 20077502, 16061562, 22006311, 26738429, 26350354, 9798686, 17550235, 9425226, 26898890, 26517685, 31159747)
Ambry Genetics RCV000115631 SCV000172787 likely benign Hereditary cancer-predisposing syndrome 2018-10-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Subpopulation frequency in support of benign classification
Invitae RCV000197696 SCV000253279 benign Familial cancer of breast 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000197696 SCV000427201 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415317 SCV000492763 uncertain significance Hereditary cancer 2014-11-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115631 SCV000682769 likely benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588281 SCV000696769 likely benign not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The BARD1 c.2282G>A (p.Ser761Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 222/129722 control chromosomes (3 homozygotes), predominantly observed in the European (Finnish) subpopulation in ExAC at a frequency of 0.0098366 (65/6608). This frequency is about 45 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in affected individuals with comparable MAF as in tested controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, without evidence for independent evaluation. Functional studies showd that variant may lead to defective BARD1 function in growth suppression and apoptosis, however, this variant is shown not to affect the HDR activity. Taken all lines of evidence together, this variant is classified as likely benign until more information becomes available.
Counsyl RCV000197696 SCV000785668 likely benign Familial cancer of breast 2017-10-26 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212144 SCV000806123 benign not specified 2017-07-11 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115631 SCV000821893 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588281 SCV000888811 benign not provided 2018-08-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000197696 SCV001368241 uncertain significance Familial cancer of breast 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357958 SCV001553572 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Ser761Asn variant was identified in 2 of 1220 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, uterine and endometrial cancers, and was present in 2 of 966 control chromosomes (frequency: 0.002) from healthy individuals (De Brakeleer 2010, Gorringe 2008, Thai 1998). The variant was also identified in dbSNP (ID: rs142155101) as “With Uncertain significance allele”, ClinVar database (1x as benign by Invitae; 3x as likely benign by GeneDx, Ambry Genetics, Illumina; 1x as uncertain significance by CMGUMCL), Clinvitae database (classified as benign by Invitae; classified as likely benign and uncertain significance by ClinVar), MutDB, Zhejiang Colon Cancer Database (LOVD), databases. This variant was identified in the genome Aggregation Database (Genome Aggregation Consortium Feb 27, 2017) in 484 (3 homozygous) of 276958 chromosomes (freq. 0.002), in the following populations: Finnish in 247 of 25792 (2 homozygous) chromosomes (freq. 0.0095), Ashkenazi Jewish in 34 of 10146 chromosomes (freq. 0.0033), European in 189 of 126482 (1 homozygous) chromosomes (freq. 0.0015), other in 7 of 6460 chromosomes (freq. 0.001), Latino in 6 of 34406 chromosomes (freq. 0.00017), African in 1 of 24028 chromosomes (freq. 0.00004), increasing the likelihood this could be a low frequency benign variant. The variant p.Ser761Asn has been identified as cancer-associated missense mutation in breast and uterine cancers (Birrane 2007). This variant was also identified in a screen of 150 sporadic tumors and was not present in normal cells of the patients, indicating that they arose somatically during tumor development (Laufer 2007). The p.Ser761Asn variant was also identified as a somatic variant in endometrial cancer patient at age 8 with associated LOH (Thai 1998).The p.Ser761Asn variant is identified as putative disease associated allele (Sauer 2005).The p.Ser761 residue is not 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 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, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. It is classified as likely benign.

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