Submissions for variant NM_000059.4(BRCA2):c.1793C>T (p.Thr598Ile)

gnomAD frequency: 0.00003  dbSNP: rs80358462

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000758865	SCV000566241	uncertain significance	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Published functional studies suggest a neutral effect: able to rescue the lethality of Brca2 null in a mESC assay (PMID: 33293522); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22034289, 29884841, 36922933, 32377563, 35980532, 31911673, 31853058, 27882536, 35585550, 35402282, 33293522)
Ambry Genetics	RCV000509597	SCV000608232	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.T598I variant (also known as c.1793C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1793. The threonine at codon 598 is replaced by isoleucine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Fackenthal JD et al. Int. J. Cancer, 2012 Sep;131:1114-23; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration was also identified in 1/527 index patients with either breast, ovarian, or pancreatic cancer (Loizidou MA et al. Clin. Genet., 2017 Apr;91:611-615). 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.
Color Diagnostics, LLC DBA Color Health	RCV000509597	SCV000688724	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 598 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). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in an individual affected with breast cancer and in a suspected hereditary breast and ovarian cancer family (PMID: 22034289, 27882536) and in a breast cancer case-control meta-analysis in one unaffected individual (1/53460) and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002676). This variant has been identified in 3/275402 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	RCV000758865	SCV000887760	uncertain significance	not provided	2019-12-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000112971	SCV001139011	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313059	SCV001503536	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 598 of the BRCA2 protein (p.Thr598Ile). This variant is present in population databases (rs80358462, gnomAD 0.02%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22034289, 27882536, 35980532). ClinVar contains an entry for this variant (Variation ID: 51195). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509597	SCV003851649	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112971	SCV003932759	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	We detected an in-frame deletion in the BRCA1 gene (c.1793C>T) which results in the substitution of the amino acid isoleucine for threonine at position 598. This mutation is considered as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112971	SCV000145937	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing