ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3995G>T (p.Gly1332Val)

dbSNP: rs730881490
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587173 SCV000210162 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing 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.
Color Diagnostics, LLC DBA Color Health RCV000580590 SCV000683142 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-05 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587173 SCV000699093 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing 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.
Invitae RCV000796595 SCV000936115 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-22 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000580590 SCV001183242 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing 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, 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.
Molecular Endocrinology Laboratory, Christian Medical College RCV001770121 SCV002004022 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000580590 SCV003849155 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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