ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: 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, susceptibility to, 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 2020-06-19 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast, prostate and other cancers and identified in an individual who had BRCA1/2 testing (Katagiri 1999, Judkins 2005, Pugh 2009); This variant is associated with the following publications: (PMID: 22476429, 31131967, 9609997, 25637381, 19638463, 15385441, 16267036, 16518693, 12531920, 15235020)
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 2021-07-19 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. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). 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 as a VUS in individuals affected with Hereditary Breast And Ovarian Cancer (example, Lu_2012, Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The expert panel has deemed a classification as benign citing the multifactorial likelihood quantitative analysis (Parsons_2019). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001344736 SCV001538812 uncertain significance Hereditary breast ovarian cancer syndrome 2021-09-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111600 SCV000144072 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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