Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.2967T>A(p.Phe989Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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 Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F989S) 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]
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23038119).
BP6
Variant 17-43092564-A-T is Benign according to our data. Variant chr17-43092564-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231629.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Apr 03, 2023
This missense variant replaces phenylalanine with leucine at codon 989 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with breast cancer or endometrial cancer (PMID: 21218378, 27443514). This variant has not been identified 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, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 07, 2014
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Oct 19, 2016
- -
Likely benign, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Jun 13, 2023
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 01, 2024
The p.F989L variant (also known as c.2967T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 2967. The phenylalanine at codon 989 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in female diagnosed with DCIS at age 28 as well as her unaffected father and considered a variant of unknown significance (Carney ME et al. Hawaii Med J 2010 Nov; 69(11):268-71). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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
Mar 22, 2023
This missense variant replaces phenylalanine with leucine at codon 989 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with breast cancer or endometrial cancer (PMID: 21218378, 27443514). This variant has not been identified 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. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 28, 2018
- -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Mar 10, 2016
This variant is denoted BRCA1 c.2967T>A at the cDNA level, p.Phe989Leu (F989L) 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 3086T>A. This variant was observed in 1/273 individuals with personal and/or family histories suspicious for Hereditary Breast and Ovarian Cancer (Carney 2010). BRCA1 Phe989Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Phe989Leu occurs at a position that is not conserved and is located in the DNA binding domain (Narod 2004) In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Phe989Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Nov 29, 2023
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 989 of the BRCA1 protein (p.Phe989Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21218378, 27443514). ClinVar contains an entry for this variant (Variation ID: 231629). 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) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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. -