Submissions for variant NM_007294.4(BRCA1):c.2808T>G (p.Asp936Glu)

gnomAD frequency: 0.00002  dbSNP: rs730881485

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590145	SCV000210135	uncertain significance	not provided	2017-09-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2808T>G at the cDNA level, p.Asp936Glu (D936E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). Using alternate nomenclature, this variant would be defined as BRCA1 2927T>G. This variant was observed in at least one individual with a personal history of ovarian cancer (Cunningham 2014). BRCA1 Asp936Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asp936Glu occurs at a position that is not conserved and is located in the DNA binding domain and region of interaction with RAD51 (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Asp936Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000471242	SCV000549334	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 936 of the BRCA1 protein (p.Asp936Glu). This variant is present in population databases (rs730881485, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 24504028). ClinVar contains an entry for this variant (Variation ID: 182149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000566633	SCV000660959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.D936E variant (also known as c.2808T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 2808. The aspartic acid at codon 936 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been identified in an individual with epithelial ovarian cancer (Cunningham J et al. Sci Rep 2014 Feb;4:4026). This alteration was also detected in a cohort of patients undergoing genetic assessment at a hereditary breast and ovarian cancer center (Chapman-Davis E et al. J Gen Intern Med, 2021 Jan;36:35-42).This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590145	SCV000698980	uncertain significance	not provided	2016-10-28	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2808T>G (p.Asp936Glu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121384 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in the literature in at least one affected individual (Cunningham_2014), without strong evidence for causality. In addition, one clinical diagnostic laboratories and a reputable database classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590145	SCV000888871	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113542 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in one or more individuals with ovarian cancer (PMID: 24504028 (2014)) and breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000566633	SCV000903172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 936 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 24504028) and in a suspected hereditary breast and ovarian family (PMID: 32720237). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005991). This variant has been identified in 5/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
MGZ Medical Genetics Center	RCV003607247	SCV002580830	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
University of Washington Department of Laboratory Medicine, University of Washington	RCV000566633	SCV003849337	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321522	SCV004026782	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing