ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1383T>A (p.Phe461Leu) (rs56046357)

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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 RCV000166450 SCV000217246 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236219 SCV000292793 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1383T>A at the cDNA level, p.Phe461Leu (F461L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTA). Using alternate nomenclature, this variant would be defined as BRCA1 1502T>A. This variant was observed in a family with breast and gastric cancer and in at least one individual with prostate cancer (Katagiri 1999, Pugh 2009). This variant was also identified in at least one individual who underwent clinical BRCA1 screening (Judkins 2005). BRCA1 Phe461Leu was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, 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, is located within the DNA binding domain and in a region reported 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 information, it is unclear whether BRCA1 Phe461Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000166450 SCV000909384 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111600 SCV000144072 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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