ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1383T>A (p.Phe461Leu) (rs56046357)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111600 SCV001161582 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000244
Ambry Genetics RCV000166450 SCV000217246 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing The p.F461L variant (also known as c.1383T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 1383. The phenylalanine at codon 461 is replaced by leucine, an amino acid with highly similar properties. This alteration has been classified as a variant of uncertain significance based on a classification system using interspecific sequence variation and has also been reported in an exome cohort (Abkevich V et al. J. Med. Genet., 2004 Jul;41:492-507; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This alteration has also been identified in one early-onset familial breast cancer kindred (<span style="background-color:initial">Katagiri T, J. Hum. Genet. 1998 ; 43(1):42-8).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Health, Inc RCV000166450 SCV000909384 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174669 SCV001337886 uncertain significance not specified 2020-01-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1383T>A (p.Phe461Leu) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1383T>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lu_2012, Judkins_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001344736 SCV001538812 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-20 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 not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with breast, ovarian, prostate and gastric cancer (PMID: 22476429, 19638463, 9609997). ClinVar contains an entry for this variant (Variation ID: 54228). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). 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.
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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