ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1771A>G (p.Ile591Val) (rs1064795358)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766775 SCV000571084 uncertain significance not provided 2016-07-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1771A>G at the cDNA level, p.Ile591Val (I591V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). Using alternate nomenclature, this variant would be defined as BRCA1 1890A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile591Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile591Val occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ile591Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000482260 SCV000591350 uncertain significance not specified 2016-07-05 criteria provided, single submitter clinical testing
Integrated 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.
Invitae RCV000821605 SCV000962370 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 591 of the BRCA1 protein (p.Ile591Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 421781). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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