Submissions for variant NM_007294.4(BRCA1):c.1384G>A (p.Gly462Arg)

gnomAD frequency: 0.00001  dbSNP: rs80357221

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047451	SCV000075464	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 462 of the BRCA1 protein (p.Gly462Arg). This variant is present in population databases (rs80357221, gnomAD 0.007%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 34326862, 34855882, 35534704). ClinVar contains an entry for this variant (Variation ID: 54230). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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	RCV000129965	SCV000184789	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-09	criteria provided, single submitter	clinical testing	The p.G462R variant (also known as c.1384G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1384. The glycine at codon 462 is replaced by arginine, an amino acid with dissimilar properties. This alteration was described as a pathogenic mutation in a French study; however, data contributing to this classification was not provided (Coulet F et al. Genet Test Mol Biomarkers. 2010; 14:677-90). This alteration was not found to have an impact on splicing using a BRCA1 minigene and RT-PCR assay (Anczukow O et al. Genes Chromosomes Cancer. 2008 May;47(5):418-26). In a functional study this alteration was shown to retain 85% of homology-directed repair activity relative to wild type (Lu C et al. Nat Commun, 2015 Dec;6:10086). This alteration was also identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000289723	SCV000329121	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: reduced, but not absent, homology-directed repair activity (Lu et al., 2015); Multifactorial analysis suggests that this variant is benign (Caputo et al., 2021); Observed in individuals with melanoma, bladder or lung cancer (Lu et al., 2015; Huang et al., 2018; Yehia et al., 2018); Also known as 1503G>A; This variant is associated with the following publications: (PMID: 18273839, 15385441, 20858050, 16518693, 15001988, 12531920, 25637381, 23704879, 23893897, 29684080, 29625052, 26689913, 34597585, 15343273)
Counsyl	RCV000077488	SCV000784902	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129965	SCV000903582	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 462 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). A functional study reported that this variant has a modest impact on BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000146) and in an individual affected with lung cancer (PMID: 26689913). This variant has been identified in 3/251048 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532904	SCV001748695	uncertain significance	not specified	2024-12-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1384G>A (p.Gly462Arg) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1384G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Anczukow_2008, Coulet_2010, Yang_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant resulted in 85%-90% of normal homology directed repair (HDR) activity (Lu_2015). In addition, a multifactorial model including cosegregation data from affected families predicted this variant to be benign (Caputo_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18273839, 34597585, 20858050, 26689913, 34855882, 36451132). ClinVar contains an entry for this variant (Variation ID: 54230). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000047451	SCV002012420	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-10-11	criteria provided, single submitter	clinical testing	The BRCA1 c.1384G>A (p.Gly462Arg) missense change has a maximum subpopulation frequency of 0.0026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41246164-C-T?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however in vitro functional studies have shown that this variant results in ~85% of homology-directed repair (HDR) activity of the BRCA1 protein compared to wild-type (PMID: 26689913). This variant has been reported in individuals with urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and skin cutaneous melanoma (PMID: 29625052). In addition, two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database https://whi.color.com/variant/17-41246164-C-T). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3, BS3.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129965	SCV003851332	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).
All of Us Research Program, National Institutes of Health	RCV000077488	SCV004818339	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 462 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). A functional study reported that this variant has a modest impact on BRCA1 function in a homology-directed repair assay (PMID: 26689913). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000146) and in an individual affected with lung cancer (PMID: 26689913). This variant has been identified in 3/251048 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000289723	SCV005626007	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	The BRCA1 c.1384G>A (p.Gly462Arg) variant has been reported in the published literature in individuals and families with breast and/or ovarian cancer (PMID: 18273839 (2008), 34855882 (2021), 34597585(2021)) and skin cutaneous melanoma (PMID: 36451132 (2022)). In a large breast cancer association study, this variant was reported both in healthy individuals and individuals with breast cancer (PMID: 33471991 (2021), see also http://databases.lovd.nl/shared/genes/BRCA1)). Additionally, functional studies have shown conflicting results of this variant's impact on DNA repair (PMID: 26689913 (2015), 34855882 (2021)). The frequency of this variant in the general population, 0.000026 (3/113478 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000077488	SCV000109286	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077488	SCV000144074	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1997-09-15	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148410	SCV000190109	uncertain significance	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004554648	SCV004708642	uncertain significance	BRCA1-related disorder	2023-10-30	no assertion criteria provided	clinical testing	The BRCA1 c.1384G>A variant is predicted to result in the amino acid substitution p.Gly462Arg. This variant has been reported in individuals with breast/ovarian cancer, bladder urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, Cowden/Cowden-like and Bannayan-Riley-Ruvalcaba syndromes (BRRS) (Anczuków et al. 2008. PubMed ID: 18273839. Table S1; Coulet et al. 2010. PubMed ID: 20858050; Lu et al. 2015. PubMed ID: 26689913. Table S12; Huang et al. 2018. PubMed ID: 29625052. Table S2B; Yehia et al. 2018. PubMed ID: 29684080. Table S9). Functional studies showed that this variant does not have an impact on splicing using a BRCA1 minigene and RT-PCR assay (Anczuków et al. 2008. PubMed ID: 18273839. Table S1) and retains 85% of wild type repair function (Lu et al. 2015. PubMed ID: 26689913. Table S22). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41246164-C-T). In ClinVar, this variant has conflicting interpretations, including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/54230/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.