Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_007294.4(BRCA1):āc.1381T>Cā(p.Phe461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F461V) has been classified as Likely benign.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Mar 26, 2019
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Uncertain significance, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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The BRCA1 p.F461L variant was reported in the literature in an individual with breast cancer and two individuals with prostate cancer (Katagiri_1998_PMID: 9609997, Pugh_2009_PMID: 19638463). The variant was identified in dbSNP (ID: rs62625300) and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and six other submitters). The variant was identified in control databases in 1 of 251080 chromosomes at a frequency of 0.000003983 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.F461 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 30, 2019
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as BRCA1 1500T>C; This variant is associated with the following publications: (PMID: 25637381, 9609997, 15235020, 16267036, 19638463, 12531920, 16518693, 10923033, 15001988, 33087888) -
Uncertain significance, criteria provided, single submitter
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 06, 2023
This variant replaces phenylalanine with leucine at codon 461 in 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 an individual affected with breast cancer (PMID: 9609997) and in a suspected hereditary breast and ovarian cancer family (PMID: 22476429). This variant also has been reported in an individual affected with prostate cancer (PMID: 19638463). This variant has been identified in 1/251080 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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 19, 2023
The p.F461L variant (also known as c.1381T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1381. The phenylalanine at codon 461 is replaced by leucine, an amino acid with highly similar properties. This alteration was previously identified in one kindred of Japanese descent with gastric and early onset breast cancer (Katagiri T et al. J. Hum. Genet. 1998; 43(1):42-8). This alteration was also identified in a high-risk breast and/or ovarian cancer family (Lu W et al. Fam Cancer, 2012 Sep;11:381-5). 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
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Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Oct 02, 2023
This variant replaces phenylalanine with leucine at codon 461 in 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 an individual affected with breast cancer (PMID: 9609997) and in a suspected hereditary breast and ovarian cancer family (PMID: 22476429). This variant also has been reported in an individual affected with prostate cancer (PMID: 19638463). This variant has been identified in 1/251080 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. -
Breast neoplasm Uncertain:1
Uncertain significance, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Jun 01, 2014
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Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
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Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Dec 18, 2023
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 (rs62625300, gnomAD 0.003%). This missense change has been observed in individual(s) with prostate cancer and breast cancer (PMID: 9609997, 19638463). ClinVar contains an entry for this variant (Variation ID: 54227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. 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. -