Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000204808 | SCV000260248 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 147 of the BRCA1 protein (p.Leu147Phe). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748876625, gnomAD 0.004%). This missense change has been observed to co-occur in individuals with a different variant in BRCA1 that has been determined to be pathogenic (PMID: 21520333, 23231788), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 220023). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 23867111, 25823446, 32546644). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, |
RCV000210978 | SCV000267682 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2016-04-21 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000221620 | SCV000275598 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-06 | criteria provided, single submitter | clinical testing | The p.L147F variant (also known as c.441G>C), located in coding exon 5 of the BRCA1 gene, results from a G to C substitution at nucleotide position 441. The leucine at codon 147 is replaced by phenylalanine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 5 and may have some effect on normal mRNA splicing. This variant was reported in a high-risk breast and ovarian cancer cohort from the Netherlands (Moghadasi S et al. J. Med. Genet., 2013 Feb;50:74-9). One literature study demonstrated this alteration may lead to intron 6 retention (Gelli E et al. Cancers (Basel), 2019 Mar;11:); however other studies have demonstrated that this alteration does not appear to cause aberrant splicing (Ambry internal data; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14). A protein functional assay found this missense alteration to be neutral (Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55). This alteration has been observed in trans in a proband with another another BRCA1 pathogenic variant without clinical presentation of Fanconi Anemia in an unpublished family pedigree (personal communication). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This amino acid position is well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000508689 | SCV000605876 | uncertain significance | not specified | 2016-08-25 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000221620 | SCV000911279 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-17 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with phenylalanine at codon 147 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). One functional study has shown the mutant protein to exhibit normal function in its ability to complement BRCA1-deficiency in mouse embryonic stem cells (PMID: 23867111), while another study has shown the mutant protein to be defective in E3 ligase activity (PMID: 25823446). In addition to the potential impact on protein function, this variant alters the highly conserved guanine nucleotide at the last nucleotide position of exon 6 and is predicted to adversely impact RNA splicing at the adjacent splice donor site in intron 6 by multiple splicing prediction tools. In a RNA study using blood samples, this variant has been shown to cause the retention of intron 6 (referred to as intron 7 in the article based on the BIC nomenclature) and predicted to result in premature protein truncation (PMID: 30832263). This aberrant transcript accounted for 34% of overall gene expression in the patient sample and was undetectable in control samples. Subsequent RNA studies have reported no significant impact of this variant on RNA splicing (PMID: 31143303; unpublished study described in ClinVar SCV000275598.4). However, details of these RNA studies are not available for review. This variant is rare in the population and has been identified in 5/281702 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been observed in individuals and/or families suspected of having hereditary breast and ovarian cancer (PMID: 23231788, 30832263; Color internal data), as well as in individuals unaffected with cancer (Color internal data). A large breast cancer case-control meta-analysis has reported the observation of this variant in 5/60466 cases and 3/53461 unaffected controls (OR=1.474, 95% CI: 0.352 to 6.167) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001287). This variant has been observed in a proband in trans with a pathogenic variant in the same gene without clinical presentation of Fanconi anemia (unpublished study described in ClinVar SCV000275598.4). In summary, the functional studies have reported conflicting results regarding the variant impact on protein function and RNA splicing, and the clinical data are insufficient to determine conclusively whether this variant is associated with disease. It cannot be ruled out that this variant may be hypomorphic and present with a reduced risk of autosomal dominant hereditary cancer compared to typical pathogenic BRCA1 variants. However, due to conflicting supporting evidence available at this time, this variant is classified as a Variant of Uncertain Significance. |
| 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: https://databases.lovd.nl/shared/variants/BRCA1#object_id=VariantOnTranscript%2CVariantOnGenome&id=BRCA1&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00003478&search_VariantOnTranscript/DNA=c.441G%3EC&page_size=100&page=1 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. |
| Gene |
RCV001753611 | SCV001985988 | uncertain significance | not provided | 2019-08-20 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23231788, 23867111, 23034506, 19370767, 25823446, 31143303, 30832263) |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000204808 | SCV004228279 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-12-19 | criteria provided, single submitter | curation | . According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose this criterium: BS3 (strong benign): Contradictory functional data regarding splice effect. Protein function not affected ( neutral Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55) Class 3 |