Submissions for variant NM_000059.4(BRCA2):c.1780A>C (p.Ile594Leu)

gnomAD frequency: 0.00001  dbSNP: rs431825287

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167234	SCV000218071	likely benign	Hereditary cancer-predisposing syndrome	2024-02-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000219220	SCV000279350	uncertain significance	not provided	2016-01-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1780A>C at the cDNA level, p.Ile594Leu (I594L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 2008A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile594Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile594Leu occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ile594Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082892	SCV000743262	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219311	SCV001391244	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 594 of the BRCA2 protein (p.Ile594Leu). This variant is present in population databases (rs431825287, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 96771). 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 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	RCV000167234	SCV003851636	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	RCV000082892	SCV004846964	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 594 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 1 individual affected with breast or ovarian cancer (DOI: 10.1515/tjb-2019-0424). This variant has been identified in 2/248072 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.
Sharing Clinical Reports Project (SCRP)	RCV000082892	SCV000114966	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000219220	SCV001906293	uncertain significance	not provided		no assertion criteria provided	clinical testing