Submissions for variant NM_007294.4(BRCA1):c.2268G>C (p.Arg756Ser)

gnomAD frequency: 0.00001  dbSNP: rs80356884

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047778	SCV000075791	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 756 of the BRCA1 protein (p.Arg756Ser). This variant is present in population databases (rs80356884, gnomAD 0.01%). This missense change has been observed in individual(s) with breast, ovarian, or prostate cancer (PMID: 16826315, 24916970, 27257965, 30702160, 34326862, 35918668). This variant is also known as 2387G>C. ClinVar contains an entry for this variant (Variation ID: 54518). 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.
Ambry Genetics	RCV000129867	SCV000184684	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	The p.R756S variant (also known as c.2268G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2268. The arginine at codon 756 is replaced by serine, an amino acid with dissimilar properties. This alteration was seen in a cohort of Portuguese breast and ovarian cancer families who were selected for BRCA1/2 screening based on clinical criteria or their BRCAPRO score and was classified as a variant of unknown significance (Peixoto A et al. Clin. Genet. 2015 Jul;88:41-8). This alteration was also identified in 1/507 unselected Chinese breast cancer patients (Zhong X et al. PLoS One. 2016 Jun;11:e0156789). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001281712	SCV000209935	likely benign	not provided	2019-06-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16826315, 24916970)
Counsyl	RCV000111812	SCV000489378	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281712	SCV000600279	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 27257965 (2016), 24916970 (2015), 16826315 (2006)). The variant has also been reported in an individual with no personal history of cancer (PMID: 31422574 (2019)). This variant is located in a region of the BRCA1 protein that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000014 (4/282606 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000129867	SCV000911273	likely benign	Hereditary cancer-predisposing syndrome	2017-08-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254635	SCV000916788	uncertain significance	not specified	2019-08-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2268G>C (p.Arg756Ser) results in a non-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. The variant allele was found at a frequency of 8e-06 in 251210 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2268G>C has been reported in the literature in individuals affected with Hereditary/familial Breast and Ovarian Cancer (Peixoto_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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129867	SCV003847798	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).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000111812	SCV004048085	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant c.2268G>C (p.R756S) in BRCA1 gene has been previously observed in 1/10076 (0.0099%) alleles from individuals of Ashkenazi Jewish background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The p.Arg756Ser variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity. The amino acid Arg at position 756 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. There is a moderate physicochemical difference between arginine and serine. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg756Ser in BRCA1 is predicted as conserved by GERP++. For these reasons, this variant has been classified as Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111812	SCV000144361	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing