ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3723T>G (p.Phe1241Leu) (rs587782723)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132213 SCV000187295 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414919 SCV000492621 uncertain significance Malignant tumor of prostate; Prostate neoplasm 2015-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000478604 SCV000566583 uncertain significance not provided 2015-05-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3723T>G at the cDNA level, p.Phe1241Leu (F1241L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). This variant, also known as BRCA2 3951T>G using alternate nomenclature,has been reported in at least two women with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011, Kanchi 2014). BRCA2 Phe1241Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Phe1241Leu occurs at a position that is conserved across species and is located in the BRC2 repeat and RAD51 binding region (Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Phe1241Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000471263 SCV000549725 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-24 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 1241 of the BRCA2 protein (p.Phe1241Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs587782723, ExAC 0.002%). This variant has been reported in an individual affected with ovarian cancer, and an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 24448499, 21120943). ClinVar contains an entry for this variant (Variation ID: 142795). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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