Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000766775 | SCV000571084 | uncertain significance | not provided | 2024-12-09 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1890A>G; This variant is associated with the following publications: (PMID: 26689913, 10426999, 10792030, 15343273, 29884841) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000482260 | SCV000916705 | uncertain significance | not specified | 2019-03-15 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.1771A>G (p.Ile591Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245912 control chromosomes (gnomAD). 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.1771A>G in individuals affected with Hereditary Breast and Ovarian Cancer 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. |
Labcorp Genetics |
RCV000821605 | SCV000962370 | benign | Hereditary breast ovarian cancer syndrome | 2023-10-18 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000766775 | SCV001133499 | uncertain significance | not provided | 2019-02-05 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001013057 | SCV001173594 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-05 | criteria provided, single submitter | clinical testing | The p.I591V variant (also known as c.1771A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1771. The isoleucine at codon 591 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. |
University of Washington Department of Laboratory Medicine, |
RCV001013057 | SCV003849746 | 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). |
Color Diagnostics, |
RCV001013057 | SCV004361050 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-01 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 591 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, protein 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 1/251084 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. |
All of Us Research Program, |
RCV004802071 | SCV005428605 | uncertain significance | BRCA1-related cancer predisposition | 2024-09-23 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 591 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). Computational RNA splicing algorithms predict the creation of a de novo splice donor site, but this had not yet been confirmed experimentally. To our knowledge, protein 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 1/251084 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. |
Department of Pathology and Laboratory Medicine, |
RCV001353541 | SCV000591350 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA1 p.Ile591Val variant was not identified in the literature nor was it identified in the in dbSNP, Clinvitae database, Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database,COSMIC, the ClinVar database, GeneInsight COGR database, the BIC database, UMD, or Fanconi Anemia (LOVD) databases. The p.Ile591 residue is not conserved in mammals, the variant amino acid Valine (Val) is present in mice and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, 4 out of 5 predict an altered 5' splice site in this region and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. 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. |