ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.716T>A (p.Leu239Gln)

gnomAD frequency: 0.00006  dbSNP: rs200359745
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212121 SCV000149551 uncertain significance not provided 2023-09-11 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: homology-directed repair activity comparable to wild type, but may cause abnormal splicing (Shirley et al., 2018; Adamovich et al., 2019); Observed in individuals with personal or family history of breast or other cancers and also in unaffected controls (Tung et al., 2016; Tsaousis et al., 2019; da Costa e Silva Carvalho et al., 2020; Dorling et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 32039725, 26976419, 26787654, 27720647, 30925164, 31159747, 31275557, 35595798, 33471991, 35264596)
Ambry Genetics RCV000115642 SCV000185658 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-14 criteria provided, single submitter clinical testing The p.L239Q variant (also known as c.716T>A), located in coding exon 4 of the BARD1 gene, results from a T to A substitution at nucleotide position 716. The leucine at codon 239 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in individuals with a personal or family history of breast and/or ovarian cancer (da Costa E Silva Carvalho S et al. BMC Med Genomics, 2020 02;13:21; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8; Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet., 2019 03;15:e1008049). RNA analyses have shown that this alteration leads to aberrant splicing by creating a new alternate donor site (Shirley BC et al. F1000Res, 2018 Dec;7:1908).This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000206495 SCV000261241 uncertain significance Familial cancer of breast 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 239 of the BARD1 protein (p.Leu239Gln). This variant is present in population databases (rs200359745, gnomAD 0.02%). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 35595798). ClinVar contains an entry for this variant (Variation ID: 127746). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine 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). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (Invitae). 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.
Counsyl RCV000206495 SCV000785164 uncertain significance Familial cancer of breast 2017-05-16 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115642 SCV000803145 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115642 SCV000821897 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000206495 SCV000837978 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212121 SCV000887602 uncertain significance not provided 2023-06-15 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26976419 (2016), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1), 35264596 (2022)), as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1)). A functional study reported that this variant has proficient homology-directed repair (HDR) activity (PMID: 30925164 (2019)). The frequency of this variant in the general population, 0.00016 (19/118622 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BARD1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics RCV000206495 SCV000895394 uncertain significance Familial cancer of breast 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115642 SCV000910706 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779824 SCV000916646 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: BARD1 c.716T>A (p.Leu239Gln) 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 0.0001 in 217412 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the expected maximum for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (0.00017 vs 0.00025), allowing no clear conclusions about variant significance. c.716T>A has been reported in the literature in individuals with a personal or family history of breast and/or ovarian cancer (e.g. Tung_2016, Tsaousis_2019, Adamovich_2019) and other tumor phenotypes (Adamovich_2019); however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reported experimental evidence demonstrating that the variant protein is fully functional in homology-directed DNA repair (HDR) (Adamovich_2019). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: nine laboratories cited the variant as uncertain significance, while one cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genetic Services Laboratory, University of Chicago RCV000779824 SCV002071335 uncertain significance not specified 2019-10-25 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115642 SCV002529646 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-17 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000206495 SCV002584573 uncertain significance Familial cancer of breast 2022-08-23 criteria provided, single submitter clinical testing The BARD1 c.716T>A (p.Leu239Gln) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 32039725, 33471991). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may affect splicing. RNA studies indicate that this variant strengthens a cryptic splice within exon 4 of the BARD1 gene and causes leaky splicing (PMID: 31275557). The in silico tool REVEL predicts a benign effect on protein function and functional analysis indicates that this variant has homology-directed repair (HDR) comparable to the wild-type (PMID: 30925164). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000779824 SCV002760251 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000206495 SCV004019266 likely benign Familial cancer of breast 2023-02-24 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492484 SCV004240150 uncertain significance Breast and/or ovarian cancer 2022-09-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004739401 SCV005356004 uncertain significance BARD1-related disorder 2024-05-01 no assertion criteria provided clinical testing The BARD1 c.716T>A variant is predicted to result in the amino acid substitution p.Leu239Gln. This variant has been reported in individuals with breast cancer (Table A2, Tung et al 2016. PubMed ID: 26976419; Table S1, Young et al. 2016. PubMed ID: 26787654; Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127746/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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