ClinVar Miner

Submissions for variant NM_000465.4(BARD1):c.2075T>C (p.Ile692Thr) (rs587782555)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131771 SCV000186817 likely benign Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000206765 SCV000261555 uncertain significance Familial cancer of breast 2020-03-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 692 of the BARD1 protein (p.Ile692Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587782555, ExAC 0.002%). This variant has been reported in a breast cancer family but was not observed to co-segregate with the disease (PMID: 17972171). ClinVar contains an entry for this variant (Variation ID: 142571). This variant has been reported not to substantially affect BARD1 protein function (PMID: 26350354). 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 RCV000521519 SCV000618456 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing This variant is denoted BARD1 c.2075T>C at the cDNA level, p.Ile692Thr (I692T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). BARD1 Ile6092Thr has been reported in an individual with breast cancer, but did not segregate with disease within the family (Gorringe 2008). This variant was found to have protein expression and homology-directed repair activity similar to wildtype (Lee 2015). BARD1 Ile692Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Ile692Thr occurs at a position that is not conserved and is located in the BRCT2 domain (Fox 2008, Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Ile692Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131771 SCV000903245 benign Hereditary cancer-predisposing syndrome 2016-02-10 criteria provided, single submitter clinical testing

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