ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.441G>C (p.Leu147Phe) (rs748876625)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000221620 SCV000275598 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-05 criteria provided, single submitter clinical testing Last nucleotide of exon;Intact protein function observed in appropriate functional assay(s);Well-characterized mutation at same position;Other data supporting pathogenic classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508689 SCV000605876 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing
Color RCV000221620 SCV000911279 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508689 SCV001160449 uncertain significance not specified 2019-04-04 criteria provided, single submitter clinical testing The BRCA1 c.441G>C; p.Leu147Phe variant (rs748876625) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Michils 2012, Moghadasi 2013), and reported multiple times in the LOVD BRCA1 database (see link). This variant is also reported in ClinVar (Variation ID: 220023). One functional study suggests the variant is neutral based on its ability to restore growth and cisplatin sensitivity in BRCA-null mouse embryonic stem cells (Bouwman 2013). However, another functional study suggests the variant is deleterious as the variant protein displays decreased E3 ligase activity compared to wild type protein (Starita 2015). This variant is found in the general population with an overall allele frequency of 0.002% (5/281702 alleles) in the Genome Aggregation Database. The leucine at codon 147 is highly conserved and the variant is located in the last nucleotide of the exon. Computational analyses (SIFT, PolyPhen-2, Alamut v.2.11) predict that this variant is deleterious and may alter splicing by weakening the nearby canonical donor splice site. However, based on available information, the significance of this variant is uncertain at this time. REFERENCES Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Link to LOVD BRCA1 database: Michils G et al. Molecular analysis of the breast cancer genes BRCA1 and BRCA2 using amplicon-based massive parallel pyrosequencing. J Mol Diagn. 2012 Nov;14(6):623-30. Moghadasi S et al. Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling. J Med Genet. 2013 Feb;50(2):74-9. Starita LM et al. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413-22.

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