17-43104122-C-G
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_007294.4(BRCA1):c.441G>C(p.Leu147Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000136 in 1,612,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L147L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense, splice_region
NM_007294.4 missense, splice_region
Scores
4
7
8
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.25
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000198 AC: 3AN: 151308Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250660Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135466
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460740Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 726676
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GnomAD4 genome 0.0000198 AC: 3AN: 151308Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2AN XY: 73856
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 04, 2019 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 25, 2016 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 11, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 01, 2024 | 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), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 220023). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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). Studies have shown this missense change is associated with multiple RNA products, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). 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. - |
| Uncertain significance, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 19, 2023 | . 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 - |
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | 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) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | BRCA1: BP1, BP4, BS3:Supporting - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2023 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
BRCA1-related cancer predisposition Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 06, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;T;T;D;D;D;D;D;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
Sift4G
Benign
T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.
Polyphen
1.0, 1.0
.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;.
Vest4
MutPred
Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP
MPC
0.44
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
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