Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130834 | SCV000185731 | uncertain significance | Hereditary cancer-predisposing syndrome | 2013-10-25 | criteria provided, single submitter | clinical testing | The p.G1062V variant (also known as c.3185G>T or 3304G>T) is located in coding exon 9 of the BRCA1 gene. This alteration results from a G to T substitution at nucleotide position 3185. The glycine at codon 1062 is replaced by valine, an amino acid with dissimilar properties. This alteration has been previously reported and classified as a variant of unknown significance (ClinVar accession RCV000031094.1 [available from www.ncbi.nlm.nih.gov/clinvar]). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.G1062V remains unclear.​ |
Gene |
RCV000485820 | SCV000566531 | uncertain significance | not provided | 2023-06-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3304G>T; This variant is associated with the following publications: (PMID: 29884841, 32377563, 15343273) |
Color Diagnostics, |
RCV000130834 | SCV000909316 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-09-29 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with valine at codon 1062 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250730 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. |
Invitae | RCV001042144 | SCV001205810 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-12-09 | 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 1062 of the BRCA1 protein (p.Gly1062Val). This variant is present in population databases (rs397507211, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 34981296). ClinVar contains an entry for this variant (Variation ID: 37513). 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. |
University of Washington Department of Laboratory Medicine, |
RCV000130834 | SCV003852352 | 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). |
Sharing Clinical Reports Project |
RCV000031094 | SCV000053690 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2012-02-24 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354784 | SCV001549481 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA1 p.Gly1062Val variant was not identified in the literature nor was it identified in the in the following databases: GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs397507211) "With Uncertain significance" allele, ClinVar (3 x, as uncertain significance by Ambry Genetics, GeneDx and SCRP), and UMD-LSDB database (1 x, as 3-UV, co-occurring with a BRCA1 variant of uncertain significance c.3086A>G, p.Asn1029Ser). The variant was also identified by our laboratory in 1 individual with a co-occurring uncertain significance variant of BRCA1 (c.3086A>G, p.Asn1029Ser), as noted in UMD database. The variant was identified in control databases in 1 of 245466 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). The p.Gly1062 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |