ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1975C>G (p.Pro659Ala) (rs587776481)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478903 SCV000573098 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1975C>G at the cDNA level, p.Pro659Ala (P659A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 2094C>G. This variant has been observed in at least one individual with prostate cancer (Leongamornlert 2012). BRCA1 Pro659Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro659Ala occurs at a position that is not conserved and is located within the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro659Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000528149 SCV000635822 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 659 of the BRCA1 protein (p.Pro659Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with prostate cancer (PMID: 22516946). ClinVar contains an entry for this variant (Variation ID: 156185). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000564764 SCV000665825 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Sharing Clinical Reports Project (SCRP) RCV000144202 SCV000189275 uncertain significance Breast-ovarian cancer, familial 1 2011-03-30 no assertion criteria provided clinical testing

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