ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1694G>A (p.Arg565His) (rs146946984)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589818 SCV000149526 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.1694G>A at the cDNA level, p.Arg565His (R565H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Also published as BARD1 1767G>A using alternate nomenclature, this variant has been observed in individuals with breast or ovarian cancer (Gorringe 2008, Ramus 2015, Tung 2015) . This variant was observed at an allele frequency of 0.2% (71/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). BARD1 Arg565His is located in the BRCT1 domain as well as the flexible linker domain (Edwards 2008, Fox 2008, UniProt). In silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BARD1 Arg565His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115617 SCV000185926 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing The p.R565H variant (also known as c.1694G>A), located in coding exon 8 of the BARD1 gene, results from a G to A substitution at nucleotide position 1694. The arginine at codon 565 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was observed in 4/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). In another study, this germline alteration was detected in 1 out of 401 sporadic breast cancer patients and was not found in 258 controls in an Australian cohort (Gorringe KL et al. Breast Cancer Res. Treat. 2008 Oct;111:505-9). This alteration has also been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam. Cancer. 2017 07;16:319-328). This amino acid position is well 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 RCV000197934 SCV000253273 likely benign Familial cancer of breast 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000197934 SCV000427209 likely benign Familial cancer of breast 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212137 SCV000600181 benign not specified 2020-03-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212137 SCV000696756 likely benign not specified 2019-05-17 criteria provided, single submitter clinical testing Variant summary: BARD1 c.1694G>A (p.Arg565His) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251836 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 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 South Asian origin. The variant, c.1694G>A, has been reported in the literature in individuals affected with breast and/or ovarian Cancer (Ramus_2015, Gorringe_2008, Yadav_2016, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication, Adamovich_2019, reported the HDR activity of the variant protein was 60% of normal. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=5), Likely benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000197934 SCV000837957 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115617 SCV000902665 likely benign Hereditary cancer-predisposing syndrome 2015-10-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000197934 SCV001367308 uncertain significance Familial cancer of breast 2019-09-16 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355455 SCV001550344 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BARD1 p.Arg565His variant was identified in 6 of 7136 proband chromosomes (frequency: 0.0008) from individuals or families with breast cancer (familial, sporadic or BRCA1/2 negative) or ovarian cancer and was not identified in 7490 control chromosomes from healthy individuals (Gorringe 2008, Ramus 2015, Yadav 2017). The variant was also identified in dbSNP (ID: rs146946984) “With Uncertain significance allele”, ClinVar (classified as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Ambry Genetics, and three other submitters). The variant was identified in control databases in 103 of 277048 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 71 of 30780 chromosomes (freq: 0.002), Ashkenazi Jewish in 13 of 10148 chromosomes (freq: 0.001), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 3 of 34418 chromosomes (freq: 0.00009), European Non-Finnish in 13 of 126568 chromosomes (freq: 0.0001), and East Asian in 2 of 18866 chromosomes (freq: 0.0001), while it was not observed in the African or Finnish populations. The p.Arg565 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 that the His variant impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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