Submissions for variant NM_007294.4(BRCA1):c.5453A>G (p.Asp1818Gly)

dbSNP: rs80357477

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215390	SCV000274108	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001095362	SCV000324810	likely pathogenic	Breast and/or ovarian cancer	2018-03-29	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031253	SCV000326317	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257937	SCV000699255	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-30	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000215390	SCV000905197	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-08	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257937	SCV001592632	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	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.
Sema4, Sema4	RCV000215390	SCV002537858	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000257937	SCV004228277	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	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)
All of Us Research Program, National Institutes of Health	RCV004802994	SCV005425569	pathogenic	BRCA1-related cancer predisposition	2024-09-16	criteria provided, single submitter	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.
Sharing Clinical Reports Project (SCRP)	RCV000031253	SCV000053857	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031253	SCV000145518	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031253	SCV001243349	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro