ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.1678A>G (p.Met560Val) (rs587780020)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206080 SCV000260314 uncertain significance Familial cancer of breast 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 560 of the BARD1 protein (p.Met560Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587780020, ExAC 0.001%). This variant has not been reported in the literature in individuals with BARD1-related disease. ClinVar contains an entry for this variant (Variation ID: 220065). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000479722 SCV000565742 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.1678A>G at the cDNA level, p.Met560Val (M560V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Met560Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BARD1 Met560Val occurs at a position that is not conserved and is located in the flexible linker and BRCT1 domains (Edwards 2008, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BARD1 Met560Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000771293 SCV000903482 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-11 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 560 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. This variant has been identified in 2/282664 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.
Ambry Genetics RCV000771293 SCV001173088 likely benign Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence

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