ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.441G>C (p.Leu147Phe) (rs748876625)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221620 SCV000275598 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing
Color RCV000221620 SCV000911279 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000204808 SCV000260248 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 147 of the BRCA1 protein (p.Leu147Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant also falls at the last nucleotide of exon 6 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748876625, ExAC frequency <0.01%). This variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 23231788). This variant has also been reported in individuals with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333); however, in two of those individuals, pathogenic alleles were also identified in BRCA1 or BRCA2, which suggests that this c.441G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 220023). One experimental study has shown that BRCA1 protein carrying this missense change restored growth and cisplatin sensitivity to BRCA1-null mouse embryonic stem cells (PMID: 23867111). However, another experimental study using a phage display assay has shown that this missense change resulted in decreased E3 ligase activity compared to wild-type protein (PMID: 25823446). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000210978 SCV000267682 uncertain significance Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508689 SCV000605876 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing

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