ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1381T>C (p.Phe461Leu) (rs62625300)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047448 SCV000075461 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 461 of the BRCA1 protein (p.Phe461Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs62625300, ExAC 0.001%). This variant has been reported in a single family affected with breast cancer (PMID: 9609997), and two individuals with prostate cancer (PMID: 19638463). ClinVar contains an entry for this variant (Variation ID: 54227). 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: "Probably 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.
Ambry Genetics RCV000215677 SCV000273103 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000679681 SCV000567587 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1381T>C at the cDNA level, p.Phe461Leu (F461L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). Using alternate nomenclature, this variant would be defined as BRCA1 1500T>C. This variant was identified in 2/39 men with a personal history of prostate cancer as well as a woman with a personal history of breast cancer and family history of breast and gastric cancer (Katagiri 1998, Pugh 2009). BRCA1 Phe461Leu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Phe461Leu occurs at a position that is conserved across species and is located within the DNA binding domain and a region known to interact with multiple 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 Phe461Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000215677 SCV000682953 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679681 SCV000806894 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764125 SCV000895098 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679681 SCV001133485 uncertain significance not provided 2019-03-26 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111599 SCV000144071 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148411 SCV000190110 uncertain significance Neoplasm of the breast 2014-06-01 no assertion criteria provided research

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