ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3995G>T (p.Gly1332Val) (rs730881490)

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Total submissions: 4
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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 RCV000580590 SCV000683142 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 and ovarian cancer syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1332 of the BRCA1 protein (p.Gly1332Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs730881490, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182156). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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