Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_007294.4(BRCA1):āc.3496G>Cā(p.Ala1166Pro) 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 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1166D) has been classified as Uncertain significance.
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.3605771).
Uncertain significance, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jan 22, 2020
The BRCA1 c.3496G>C; p.Ala1166Pro variant (rs745418679), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 216663). This variant is found on a single chromosome in the Genome Aggregation Database (1/251294 alleles), indicating it is not a common polymorphism. The alanine at codon 1166 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Ala1166Pro variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Feb 16, 2021
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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3615G>C -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 29, 2023
The p.A1166P variant (also known as c.3496G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 3496. The alanine at codon 1166 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a cohort of 524 Chinese breast cancer patients (Chen B et al. Aging (Albany NY), 2020 Feb;12:3140-3155). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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). -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Feb 21, 2015
In summary, this is a missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been published in the literature and has only been reported once in population databases (no rsID). This sequence change replaces alanine with proline at codon 1166 of the BRCA1 protein (p.Ala1166Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. -