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

gnomAD frequency: 0.00001  dbSNP: rs56046357

Total submissions: 7

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	2021-05-05	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 also been identified in an early-onset familial breast cancer kindred (Katagiri T, J. Hum. Genet. 1998; 43(1):42-8), another family with breast and/or ovarian cancer (Lu W et al. Fam Cancer, 2012 Sep;11:381-5), and a patient with prostate cancer (Pugh TJ et al. Clin Cancer Res, 2009 Aug;15:5008-16). 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	2022-11-23	criteria provided, single submitter	clinical testing	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 et al., 1999; Judkins et al., 2005; Pugh et al., 2009; Lu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1502T>A; This variant is associated with the following publications: (PMID: 9609997, 22476429, 16267036, 15343273, 31131967, 19638463, 15235020, 12531920, 16518693, 15385441, 25637381)
Color Diagnostics, LLC DBA Color Health	RCV000166450	SCV000909384	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 461 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two families suspected of hereditary breast and/or ovarian cancer (PMID: 9609997, 22476429) and in an individual affected with prostate cancer (PMID: 19638463). A multifactorial analysis has reported likelihood ratios for pathogenicity based on segregation, co-occurrence with a pathogenic variant and family history of 0.0048, 1.256 and 1.9867, respectively (PMID: 31131967). This variant has been identified in 1/31410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the BRCA1 protein (p.Phe461Leu). This variant is present in population databases (rs56046357, gnomAD 0.007%). This missense change has been observed in individual(s) with breast, ovarian, prostate and gastric cancer (PMID: 9609997, 19638463, 22476429). ClinVar contains an entry for this variant (Variation ID: 54228). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or 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, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing