ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5216A>T (p.Asp1739Val) (rs80357227)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000614231 SCV000733594 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
GeneDx RCV000520251 SCV000617446 likely pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5216A>T at the cDNA level, p.Asp1739Val (D1739V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 5335A>T. This variant has been observed in at least two ovarian cancer patients with a family history of breast and/or ovarian cancer (Laplace-Marieze 1999, Ricevuto 2001). In functional studies this variant displayed impaired structural stability, binding activity, binding specificity, protein folding, transcription activity, cisplatin response, and ability to support growth (Lee 2010, Bouwman 2013). BRCA1 Asp1739Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1739Val occurs at a position that is conserved in mammals and is located in the region of interaction with BRCA2 and multiple other proteins (Chen 1998, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider BRCA1 Asp1739Val to be a likely pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000614231 SCV000743376 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508631 SCV000605908 uncertain significance not specified 2016-08-10 criteria provided, single submitter clinical testing

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