ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3088T>G (p.Phe1030Val) (rs80358554)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165765 SCV000216510 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077291 SCV000146168 uncertain significance Breast-ovarian cancer, familial 2 2000-08-16 no assertion criteria provided clinical testing
Color RCV000165765 SCV000688785 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
GeneDx RCV000214139 SCV000278844 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3088T>G at the cDNA level, p.Phe1030Val (F1030V) at the protein level, and results in the change of a Phenylalanine to a Valine (TTC>GTC). Using alternate nomenclature, this variant would be defined as BRCA2 3316T>G. A cDNA-based investigation, following identification of this variant in at least one individual with a history suggestive of hereditary breast and ovarian cancer, determined that this variant did not demonstrate allelic imbalance (Caux-Moncoutier 2009); however, follow-up confirmatory studies have not been published, to our knowledge. BRCA2 Phe1030Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Valine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Phe1030Val occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is located in the BRC1 domain and RAD51 binding domain (Cole 2011, Roy 2012). 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 BRCA2 Phe1030Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000044116 SCV000072129 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 1030 of the BRCA2 protein (p.Phe1030Val). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (rs80358554, ExAC no frequency). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 19471317), as well as an individual with early-onset breast cancer (Invitae). However, in the latter individual a pathogenic allele was also identified in BRCA2, which suggests that this c.3088T>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51397). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000044116 SCV000838783 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214139 SCV000889016 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077291 SCV000109088 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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