ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5425G>T (p.Val1809Phe) (rs28897698)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235944 SCV000293325 likely pathogenic not provided 2015-10-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5425G>T at the cDNA level, p.Val1809Phe (V1809F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant, also reported as BRCA1 5544G>T using alternate nomenclature, has been observed in families with breast and/or ovarian cancer and was shown to segregate with breast cancer in four individuals in one family (Phelan 2005, Thomassen 2008). Transcriptional assays in yeast and mammalian cells show a significant decrease in transcription when compared to wild type while the majority of in vitro assays demonstrate reduced peptide binding activity and specificity (Williams 2003, Williams 2004, Phelan 2005, Glover 2006, Drikos 2009, Lee 2010). BRCA1 Val1809Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Val1809Phe occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the BRCT2 domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider BRCA1 Val1809Phe to be a likely pathogenic variant.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112651 SCV000145509 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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