ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4639T>G (p.Leu1547Val) (rs730881492)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589558 SCV000699160 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4639T>G (p.Leu1547Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Variant is not in any known functional domain of the protein (InterPro). This variant is absent in 121378 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics RCV001022825 SCV001184604 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-16 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001218897 SCV001390805 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-06-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1547 of the BRCA1 protein (p.Leu1547Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine 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: 496386). 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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