Submissions for variant NM_007294.4(BRCA1):c.5453A>G (p.Asp1818Gly) (rs80357477)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215390	SCV000274108	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	The p.D1818G 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). Further, functional studies using RT-PCR on cDNA have demonstrated complete, allele-specific exon-skipping resulting in a frameshift impacting the second BRCT domain of BRCA1 (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). Another functional assay determined the p.D1818G variant to be a loss of function allele (Findlay GM et al. Nature. 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 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 and 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 Health, Inc	RCV000215390	SCV000905197	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	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.
Invitae	RCV000257937	SCV001592632	pathogenic	Hereditary breast and ovarian cancer syndrome	2020-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glycine at codon 1818 of the BRCA1 protein (p.Asp1818Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with unspecified or breast and/or ovarian cancer (PMID: 20875879, 22505045, 29446198). ClinVar contains an entry for this variant (Variation ID: 37672). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 20516115, 30209399). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20875879, 22505045, 30209399). Transcriptional studies using RT-PCR analysis of mRNA isolated from lymphocytes from affected individuals show that this variant results in complete skipping of exon 22 (also known as exon 23 in the literature), and a truncated protein product (p.Gly1803GlnfsX11) (PMID: 20875879, 22505045). This truncation disrupts the C-terminal BRCT domain of the BRCA1 protein, which is important for DNA repair activity (PMID: 14576433, 15133503). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories	RCV001659906	SCV001878778	likely benign	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031253	SCV000053857	pathogenic	Breast-ovarian cancer, familial 1	2010-12-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031253	SCV000145518	uncertain significance	Breast-ovarian cancer, familial 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute,University of Washington	RCV000031253	SCV001243349	not provided	Breast-ovarian cancer, familial 1		no assertion provided	in vitro