Submissions for variant NM_007294.4(BRCA1):c.287A>G (p.Asp96Gly)

dbSNP: rs864622444

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203904	SCV000260660	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-14	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 220258). This missense change has been observed in individual(s) with breast and/or ovarian cancer (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 96 of the BRCA1 protein (p.Asp96Gly).
Color Diagnostics, LLC DBA Color Health	RCV001180532	SCV001345475	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 96 in the RING domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant to be defective in ubiquitin E3 ligase, BARD1 binding and haploid cell proliferation assays (PMID: 25823446, 30209399). This variant has been reported in multiple unrelated individuals affected with ovarian or breast cancer, with family history of ovarian or breast cancer in the first-degree relatives (Clinvar accession ID: SCV000260660.3; communication with an external laboratory) . 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 Likely Pathogenic.
Ambry Genetics	RCV001180532	SCV002749569	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The p.D96G variant (also known as c.287A>G), located in coding exon 4 of the BRCA1 gene, results from an A to G substitution at nucleotide position 287. The aspartic acid at codon 96 is replaced by glycine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Additional alterations at the same codon have also been found to cause loss of function and have been detected in individuals with breast and/or ovarian cancer (Findlay GM et al. Nature, 2018 10;562:217-222; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002500651	SCV002810327	likely pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-04-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001077807	SCV004018672	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35659930]. This variant is expected to disrupt protein structure [Myriad internal data].
Brotman Baty Institute, University of Washington	RCV001077807	SCV001243794	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro