Submissions for variant NM_007294.4(BRCA1):c.851A>G (p.Gln284Arg)

dbSNP: rs80357039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281716	SCV000600444	uncertain significance	not provided	2021-08-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563578	SCV000661120	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The p.Q284R variant (also known as c.851A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 851. The glutamine at codon 284 is replaced by arginine, an amino acid with highly similar properties. One study found this alteration in 1/110 Hispanic individuals with personal or family history of breast and/or ovarian cancer, and it was called an unclassified variant (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71). This alteration was also detected in another study of 1/1197 patients with breast cancer who underwent genetic testing (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). In a study that utilized comparative evolutionary methods, this alteration was predicted to affect protein function due to its location at a fixed site (Fleming MA et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Feb;100:1151-6). In another study, a novel method that incorporated site-specific selection level as well as the severity of the amino acid change was used to rank the oncogenic risk of BRCA1 missense variants, and p.Q284R was not expected to confer high oncogenic risk (Burk-Herrick A et al. Mamm. Genome, 2006 Mar;17:257-70). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507601	SCV000699319	uncertain significance	not specified	2019-07-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.851A>G (p.Gln284Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Studies based on comparative phylogenetics (Fleming_2003, Burk-Herrick_2005) predicted that an amino acid change at this position could potentially affect protein function as this residue is highly conserved across several species, but these predictions have not been confirmed by published functional studies. The variant was absent in 251110 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.851A>G, has been reported in the literature in one individual affected with breast and/ or ovarian cancer (Weitzel_2005). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic BRCA1 variant have been reported (c.4327C>T, p.Arg1443X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV000764126	SCV000895099	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563578	SCV001342716	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 284 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been reported in an individual affected with breast cancer in the literature (PMID 16030099). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370720	SCV001567249	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 284 of the BRCA1 protein (p.Gln284Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 16030099, 34284872). ClinVar contains an entry for this variant (Variation ID: 55739). 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.
GeneDx	RCV001281716	SCV001802037	uncertain significance	not provided	2019-10-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect: results in impaired E3 ligase activity (Starita 2015); Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Weitzel 2005); Also known as 970A>G; This variant is associated with the following publications: (PMID: 25823446, 10923033, 12531920, 16030099, 16518693)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563578	SCV003847897	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112804	SCV000145705	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing