Submissions for variant NM_007294.3(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	2018-07-10	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	2016-02-25	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: 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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