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

gnomAD frequency: 0.00006  dbSNP: rs200359745

Total submissions: 17

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	2022-07-28	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	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