ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1439T>C (p.Leu480Ser)

gnomAD frequency: 0.00002  dbSNP: rs149839922
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166238 SCV000217018 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-02 criteria provided, single submitter clinical testing The p.L480S variant (also known as c.1439T>C), located in coding exon 6 of the BARD1 gene, results from a T to C substitution at nucleotide position 1439. The leucine at codon 480 is replaced by serine, an amino acid with dissimilar properties. In a homology-directed repair (HDR) assay, this alteration showed HDR activity below the cutoff for proficiency (Adamovich AI et al. PLoS Genet. 2019 03;15(3):e1008049). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000236389 SCV000293678 uncertain significance not provided 2023-07-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate significantly reduced homology-directed repair (HDR) activity compared to wildtype (Adamovich et al., 2019); This variant is associated with the following publications: (PMID: 23056176, 30804502, 31871109, 30925164, 18480049)
Color Diagnostics, LLC DBA Color Health RCV000166238 SCV000682692 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-29 criteria provided, single submitter clinical testing This missense variant replaces leucine with serine at codon 480 of the BARD1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit significantly reduced homology-directed repair activity (PMID: 30925164). This variant has been reported in an individual affected with breast cancer (PMID: 31871109). This variant has been identified in 5/282726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). All five of these alleles were observed in the African population in the non-cancer cohort (5/23616). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000635855 SCV000757280 uncertain significance Familial cancer of breast 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the BARD1 protein (p.Leu480Ser). This variant is present in population databases (rs149839922, 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: 186616). 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. Experimental studies have shown that this missense change affects BARD1 function (PMID: 30925164). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800498 SCV002047069 uncertain significance not specified 2021-05-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000635855 SCV004214967 uncertain significance Familial cancer of breast 2024-03-26 criteria provided, single submitter clinical testing

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