Submissions for variant NM_007294.4(BRCA1):c.2798G>C (p.Gly933Ala)

dbSNP: rs80356941

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000989896	SCV001161496	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00015
Ambry Genetics	RCV000216171	SCV000277632	likely benign	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000486989	SCV000572402	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2798G>C at the cDNA level, p.Gly933Ala (G933A) at the protein level, and results in the change of a Glycine to an Alanine (GGT>GCT). Using alternate nomenclature, this variant would be defined as BRCA1 2917G>C. This variant was observed in at least one family with breast and/or ovarian cancer (Lu 2012). BRCA1 Gly933Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly933Ala occurs at a position that is not conserved and is located within the DNA binding domain and in a region that binds RAD51 (Chen 1998, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Gly933Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000548703	SCV000635865	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000989896	SCV001140569	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216171	SCV001339691	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 933 of the BRCA1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤ 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000486989	SCV001716306	uncertain significance	not provided	2020-11-30	criteria provided, single submitter	clinical testing