Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_007294.4(BRCA1):c.4396A>T(p.Ser1466Cys) 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 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 2 ACMG points.
PM1
In a compositionally_biased_region Polar residues (size 28) in uniprot entity BRCA1_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14668763).
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Uncertain:1
Apr 20, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.4396A>T at the cDNA level, p.Ser1466Cys (S1466C) at the protein level, and results in the change of a Serine to a Cysteine (AGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 4515A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser1466Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1466Cys occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Chen 1998). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1466Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.S1466C variant (also known as c.4396A>T), located in coding exon 12 of the BRCA1 gene, results from an A to T substitution at nucleotide position 4396. The serine at codon 1466 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Jul 06, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1466 of the BRCA1 protein (p.Ser1466Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 420981). 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. 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. -