Submissions for variant NM_000059.4(BRCA2):c.2024C>G (p.Thr675Arg)

dbSNP: rs80358484

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168556	SCV000071948	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 675 of the BRCA2 protein (p.Thr675Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51236). 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) indicates that this missense variant is not expected to disrupt BRCA2 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	RCV000222018	SCV000276242	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	The p.T675R variant (also known as c.2024C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2024. The threonine at codon 675 is replaced by arginine, an amino acid with similar properties. 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 this alteration remains unclear.
GeneDx	RCV000481560	SCV000569252	uncertain significance	not provided	2024-02-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 2252C>G; This variant is associated with the following publications: (PMID: 23704879, 31131967, 29884841, 32377563)
Counsyl	RCV000113006	SCV000785208	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222018	SCV000906887	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 675 of the BRCA2 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 a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.7027 respectively (PMID: 31131967). 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.
MGZ Medical Genetics Center	RCV003607209	SCV002579529	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
University of Washington Department of Laboratory Medicine, University of Washington	RCV000222018	SCV003846446	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) (BRCA2)	RCV000113006	SCV000145992	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing