ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3267G>T (p.Leu1089Phe) (rs767544239)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563038 SCV000673058 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000563038 SCV000904124 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781005 SCV000918753 uncertain significance not specified 2017-12-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3267G>T (p.Leu1089Phe) variant involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in 2/276164 control chromosomes (gnomAD) at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). 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.
Invitae RCV000814517 SCV000954930 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1089 of the BRCA1 protein (p.Leu1089Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs767544239, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 485399). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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