Submissions for variant NM_007294.4(BRCA1):c.2021C>G (p.Pro674Arg)

dbSNP: rs876660543

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215962	SCV000278064	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-27	criteria provided, single submitter	clinical testing	The p.P674R variant (also known as c.2021C>G and 2140C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2021. The proline at codon 674 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is poorly 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 p.P674R remains unclear.
GeneDx	RCV000484472	SCV000570804	uncertain significance	not provided	2016-06-28	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2021C>G at the cDNA level, p.Pro674Arg (P674R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). Using alternate nomenclature, this variant would be defined as BRCA1 2140C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro674Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro674Arg occurs at a position that is not conserved and is located within the DNA binding domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Pro674Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000695958	SCV000824499	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-12-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 233643). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 674 of the BRCA1 protein (p.Pro674Arg).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215962	SCV003849562	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).