ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4639T>A (p.Leu1547Met) (rs730881492)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159993 SCV000210180 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4639T>A at the cDNA level, p.Leu1547Met (L1547M) at the protein level, and results in the change of a Leucine to a Methionine (TTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 4758T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1547Met was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu1547Met occurs at a position that is not conserved and is located in a region that interacts with multiple proteins (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 Leu1547Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637631 SCV000759098 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 1547 of the BRCA1 protein (p.Leu1547Met). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and methionine. 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: 182162). 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.
Ambry Genetics RCV001022824 SCV001184603 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing Insufficient evidence

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