ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.668A>G (p.Glu223Gly)

gnomAD frequency: 0.00022  dbSNP: rs145009419
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587223 SCV000149548 uncertain significance not provided 2022-01-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair activity similar to wild-type (Adamovich 2019); This variant is associated with the following publications: (PMID: 23056176, 27742771, 25980754, 26976419, 26898890, 27443514, 28873162, 25186627, 30925164, 27535533)
Ambry Genetics RCV000115639 SCV000186665 likely benign Hereditary cancer-predisposing syndrome 2020-05-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000198939 SCV000254585 uncertain significance Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 223 of the BARD1 protein (p.Glu223Gly). This variant is present in population databases (rs145009419, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer or clinical features of Lynch syndrome (PMID: 25186627, 25980754, 26976419). ClinVar contains an entry for this variant (Variation ID: 127743). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). 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.
Fulgent Genetics,Fulgent Genetics RCV000198939 SCV000611373 uncertain significance Familial cancer of breast 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855630 SCV000696783 likely benign not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: BARD1 c.668A>G (p.Glu223Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 229148 control chromosomes, predominantly at a frequency of 0.00032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.668A>G has been reported in the literature in individuals with suspected Lynch syndrome, affected with breast cancer and endometrial cancer without strong evidence of causality (Tung_2015, Yurgelun_2015, Ring_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (CHEK2 c.1100del , p.Thr367Metfs*15), for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x uncertain significance and 1x likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000198939 SCV000785710 uncertain significance Familial cancer of breast 2017-11-07 criteria provided, single submitter clinical testing
Mendelics RCV000198939 SCV000837979 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115639 SCV000902661 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587223 SCV001469362 likely benign not provided 2020-08-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000855630 SCV002065690 uncertain significance not specified 2021-08-30 criteria provided, single submitter clinical testing DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.668A>G, in exon 4 that results in an amino acid change, p.Glu223Gly. This sequence change has been described in the gnomAD database with frequency of 0.033% in the non-Finnish European subpopulation (dbSNP rs145009419). The p.Glu223Gly change affects a moderately conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Glu223Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in individuals who underwent germline genetic testing based on a personal history of breast cancer or a Lynch syndrome-associated cancer (PMID: 26976419, 25980754). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu223Gly change remains unknown at this time.
Sema4,Sema4 RCV000115639 SCV002529642 likely benign Hereditary cancer-predisposing syndrome 2020-10-18 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV000198939 SCV002578894 uncertain significance Familial cancer of breast 2022-03-22 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355551 SCV001550471 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Glu223Gly variant was identified in 2 of 3496 proband chromosomes (frequency 0.00057) from American individuals with Lynch syndrome-associated cancer and/or polyps and breast cancer (Yurgelun_2015_25980754, Tung_2016_26976419). The variant was also identified in dbSNP (ID: rs145009419) as “With Uncertain significance allele”, ClinVar and Clinvitae (4x classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Fulgent Genetics), and the Zhejiang Colon Cancer Database (1 entry, pathogenicity unknown). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 41 of 255258 chromosomes at a frequency of 0.00016 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23436 chromosomes (freq: 0.000043), European Non-Finnish in 38 of 120160 chromosomes (freq: 0.00032), European Finnish in 2 of 25186 chromosomes (freq: 0.00008); it was not observed in the “Other”, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Glu223Gly residue is conserved in mammals but not in more distantly related organisms, however, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, but 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.