Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_007294.4(BRCA1):c.4097G>A(p.Gly1366Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 3 ACMG points.
PM1
In a compositionally_biased_region Polar residues (size 33) in uniprot entity BRCA1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4151625).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.4097G>A (p.Gly1366Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant also alters a conserved first coding nucleotide of exon 11 adjacent to the penultimate intronic canonical splice acceptor site. 4/4 computational tools predict no significant impact on normal splicing. An additional prediction protocol named splicing prediction in consensus elements (SPiCE) has also reported no impact on splicing (Leman_2018). Consistently, the variant was not reported to be associated with an impact on mRNA splicing using an in-vitro assay (Colombo_2013). The variant was absent in 247322 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4097G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Mar 04, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces glycine with aspartic acid at codon 1366 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown this variant had no impact on mRNA splicing and demonstrated bi-allelic expression of the normal transcript (PMID: 23451180). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.G1366D variant (also known as c.4097G>A) is located in coding exon 10 of the BRCA1 gene. The glycine at codon 1366 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 10. In one functional study, normal mRNA splicing was observed for this alteration and sequence analysis of cDNA revealed bi-allelic expression of normal transcript (Colombo M et al. Science. PLoS One. 2013;8(2):e57173). This amino acid position is well conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other 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
Mar 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1366 of the BRCA1 protein (p.Gly1366Asp). 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: 234236). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change does not affect mRNA splicing (PMID: 23451180). 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. -