Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate
The ENST00000357654.9(BRCA1):c.3995G>T(p.Gly1332Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1332R) 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]
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
Jan 05, 2021
This missense variant replaces glycine with valine at codon 1332 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 an individual affected with breast cancer (PMID: 31477031). This variant has been identified in 2/251224 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
Jul 09, 2018
The p.G1332V variant (also known as c.3995G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3995. The glycine at codon 1332 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is poorly 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. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
May 20, 2016
Variant summary: The BRCA1 c.3995G>T (p.Gly1332Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/121390 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). One clinical diagnostic laboratory classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. In one internal sample, it was found to co-occur with another pathogenic variant MSH2 c.942+3A>T, suggesting it may be possibly benign. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Oct 02, 2018
This variant is denoted BRCA1 c.3995G>T at the cDNA level, p.Gly1332Val (G1332V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA). Using alternate nomenclature, this variant would be defined as BRCA1 4114G>T. This variant has been observed in at least one individual with advanced cancer (Mandelker 2017). BRCA1 Gly1332Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Clark 2012, Paul 2014). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice site.? However, in the absence of RNA or functional studies, the actual effect of this variant is unknown.? Based on currently available evidence, it is unclear whether BRCA1 Gly1332Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Molecular Endocrinology Laboratory, Christian Medical College
-
- -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 22, 2023
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1332 of the BRCA1 protein (p.Gly1332Val). This variant is present in population databases (rs730881490, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 31477031). ClinVar contains an entry for this variant (Variation ID: 182156). 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. -