Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.5453A>G(p.Asp1818Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
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]
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.78
PP5
Variant 17-43047657-T-C is Pathogenic according to our data. Variant chr17-43047657-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43047657-T-C is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.D1818G pathogenic variant (also known as c.5453A>G), located in coding exon 21 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5453. The aspartic acid at codon 1818 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in multiple high-risk breast/ovarian cancer families (Rouleau E et al. Cancer Genet Cytogenet. 2010 Oct; 202(2):144-6; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested and result in allele-specific skipping of coding exon 22 which is predicted to result in a frameshift with loss of a critical portion of the BRCT domain of BRCA1 (Ambry internal data; Rouleau E et al. Cancer Genet Cytogenet. 2010 Oct; 202(2):144-6; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Mar 06, 2022
Sema4, Sema4
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation
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Dec 21, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces aspartic acid with glycine at codon 1818 of the BRCA1 protein. An RNA study has shown that this variant resulted in the full skipping of exon 22 in carrier RNA, which is predicted to disrupt of the C-terminal portion of the protein including the functionally important second BRCT domain (PMID: 20875879). A functional study has shown that this variant caused loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least four individuals affected with high-risk breast cancer (PMID: 20875879; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1818 of the BRCA1 protein (p.Asp1818Gly). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20875879, 22505045, 29446198). ClinVar contains an entry for this variant (Variation ID: 37672). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Studies have shown that this missense change results in skipping of exon 22 (also known as exon 23 in the literature) and introduces a new termination codon (PMID: 20875879, 22505045). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect on BRCA1 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. For these reasons, this variant has been classified as Pathogenic. -
Jun 30, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5453A>G (p.Asp1818Gly) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251488 control chromosomes. c.5453A>G has been reported in the literature in multiple families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rouleau_2010, Rebbeck_2018, Parsons_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the predicted amino acid change has limited effects on protein function (e.g. Lee_2010, Fernandes_2019). However, several additional publications report that the variant has an effect on mRNA splicing, resulting in a frameshift and premature stop codon (producing the protein change p.Gly1803GlnfsX11 and resulting in skipping of exon 23), rather than the predicted missense change (e.g. Rouleau_2010, Houdayer_2012, Wai_2020). These findings provide additional evidence for a pathogenic effect. Five ClinVar submitters (evaluation after 2014; including one expert panel) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Dec 19, 2023
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation
conflicting functional and genetic data. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PVS1 (medium pathogenic): RNA studies have demonstrated abnormal splicing in the set of samples tested and result in allele-specific skipping of coding exon 22 which is predicted to result in a frameshift with loss of a critical portion of the BRCT domain of BRCA1 (Ambry internal data; Rouleau E et al. Cancer Genet Cytogenet. 2010 Oct; 202(2):144-6; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38)., PS3 (strong pathogenic): Findlay et al. LOF Table9_BRCA12VCEP_specs, PM2 (supporting pathogenic): absent from controls, BP5 (supporting benign): LR: 0.34 (Parsons et al, 2019) -
Breast and/or ovarian cancer Pathogenic:1
Mar 29, 2018
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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BRCA1-related cancer predisposition Pathogenic:1
Sep 16, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces aspartic acid with glycine at codon 1818 of the BRCA1 protein. RNA studies have shown that this variant resulted in the skipping of exon 22 in carrier RNA, which is predicted to disrupt the functionally important BRCT domain (PMID: 20875879, 32123317). A functional study has shown that this variant caused loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least four individuals affected with high-risk breast cancer (PMID: 20875879; Color internal data). Multifactorial analyses have reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and personal and family history, reaching a combined LR greater than 3:1 (PMID: 31131967, 31853058; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -