ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.716T>A (p.Leu239Gln) (rs200359745)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212121 SCV000149551 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.716T>A at the cDNA level, p.Leu239Gln (L239Q) at the protein level, and results in the change of a Leucine to a Glutamine (CTG>CAG). This variant has been observed in at least one individual with breast cancer (Tung 2016). BARD1 Leu239Gln was observed at an allele frequency of 0.02% (19/11,6038) in individuals of European ancestry in large population cohorts (Lek 2016). Since Leucine and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Leu239Gln is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BARD1 Leu239Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115642 SCV000185658 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-13 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.
Invitae RCV000206495 SCV000261241 uncertain significance Familial cancer of breast 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 239 of the BARD1 protein (p.Leu239Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is present in population databases (rs200359745, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed individuals with personal or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747). ClinVar contains an entry for this variant (Variation ID: 127746). 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.
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 2019-07-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000206495 SCV000895394 uncertain significance Familial cancer of breast 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc 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.

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