Submissions for variant NM_007294.4(BRCA1):c.3220A>G (p.Arg1074Gly)

gnomAD frequency: 0.00001  dbSNP: rs80357263

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221174	SCV000276311	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-18	criteria provided, single submitter	clinical testing	The p.R1074G variant (also known as c.3220A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3220. The arginine at codon 1074 is replaced by glycine, an amino acid with dissimilar properties. Based on comparative evolutionary conservation analyses, this alteration was predicted to be possibly deleterious (Fleming MA et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Feb;100(3):1151-6; Ramirez CJ et al. Oncogene 2004 Mar;23(9):1780-8; Burck-Herrick et al. Mamm. Genome 2006 Mar;17(3):257-70). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000767060	SCV000565924	uncertain significance	not provided	2024-03-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3339A>G; This variant is associated with the following publications: (PMID: 15001988, 16518693, 16267036, 12531920, 15343273, 31131967, 33087888)
Department of Pathology and Molecular Medicine, Queen's University	RCV000485156	SCV000588044	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221174	SCV001345923	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 1074 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 individuals who underwent hereditary cancer testing (PMID: 16267036, 33875564) and found to have a family history likelihood ratio for pathogenicity of 0.2793 (PMID: 31131967). This variant has been identified in 3/281800 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054874	SCV002410032	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000221174	SCV003850787	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767060	SCV004219345	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in a cohort of at-risk or affected individuals with breast cancer (PMID: 16267036 (2005)). A large scale multifactorial study described the variant as being likely benign (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.00012 (3/24964 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
All of Us Research Program, National Institutes of Health	RCV000112031	SCV004815588	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 1074 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 individuals who underwent hereditary cancer testing (PMID: 16267036, 33875564) and found to have a family history likelihood ratio for pathogenicity of 0.2793 (PMID: 31131967). This variant has been identified in 3/281800 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112031	SCV000144679	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1997-02-15	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000112031	SCV004228347	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)