Submissions for variant NM_000465.4(BARD1):c.54C>G (p.Asn18Lys)

gnomAD frequency: 0.00001  dbSNP: rs587780032

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766538	SCV000149545	uncertain significance	not provided	2023-01-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31036035)
Ambry Genetics	RCV000115636	SCV000184256	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	The p.N18K variant (also known as c.54C>G), located in coding exon 1 of the BARD1 gene, results from a C to G substitution at nucleotide position 54. The asparagine at codon 18 is replaced by lysine, an amino acid with similar properties. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766538	SCV000600199	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals with BARD1-related conditions in the published literature. The frequency of this variant in the general population, 0.00022 (4/17842 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae	RCV000535960	SCV000633044	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 18 of the BARD1 protein (p.Asn18Lys). This variant is present in population databases (rs587780032, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 127740). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000535960	SCV000786449	uncertain significance	Familial cancer of breast	2018-05-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000535960	SCV000896923	uncertain significance	Familial cancer of breast	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115636	SCV000903479	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 18 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature but has been reported in an unaffected individual in a breast cancer case-control study (PMID: 31036035). This variant has been identified in 4/246038 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731379	SCV001983475	uncertain significance	not specified	2021-09-04	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.54C>G (p.Asn18Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 214678 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.54C>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000766538	SCV002009138	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153370	SCV003843300	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000535960	SCV004019258	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].
PreventionGenetics, part of Exact Sciences	RCV003935101	SCV004761773	uncertain significance	BARD1-related disorder	2024-02-05	criteria provided, single submitter	clinical testing	The BARD1 c.54C>G variant is predicted to result in the amino acid substitution p.Asn18Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127740/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.