Submissions for variant NM_007294.4(BRCA1):c.2468G>T (p.Arg823Ile)

gnomAD frequency: 0.00001  dbSNP: rs876659731

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217280	SCV000276513	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.R823I variant (also known as c.2468G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2468. The arginine at codon 823 is replaced by isoleucine, an amino acid with similar properties. This alteration was previously reported in at least one individual from a cohort of 278 individuals with early-onset breast cancer (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590056	SCV000698957	uncertain significance	not specified	2019-02-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2468G>T (p.Arg823Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245586 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2468G>T has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Maxwell_2015), along with a reported somatic occurrence (Giannakis_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000217280	SCV000904776	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 823 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 breast cancer (PMID: 25503501). 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	RCV001853587	SCV002184570	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 823 of the BRCA1 protein (p.Arg823Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 232385). 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. 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.
Mendelics	RCV000590056	SCV002516969	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000217280	SCV003847647	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	RCV003997968	SCV004818179	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 823 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 breast cancer (PMID: 25503501). 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.