ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.460G>A (p.Val154Ile) (rs1064793318)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487073 SCV000565764 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.460G>A at the cDNA level, p.Val154Ile (V154I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). Using alternate nomenclature, this variant would be defined as BRCA1 579G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val154Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val154Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the region of interaction with BRD7 (Harte 2010). 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 Val154Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000809375 SCV000949525 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 154 of the BRCA1 protein (p.Val154Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 418595). 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 isoleucine 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. 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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