Submissions for variant NM_000059.4(BRCA2):c.5335G>A (p.Val1779Ile)

dbSNP: rs431825329

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231399	SCV000283261	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1779 of the BRCA2 protein (p.Val1779Ile). This variant is present in population databases (rs431825329, gnomAD 0.01%). 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: 96819). 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.
GeneDx	RCV000486253	SCV000571901	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5335G>A at the cDNA level, p.Val1779Ile (V1779I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 5563G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val1779Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val1779Ile occurs at a position that is not conserved and is located in the region of interaction with RAD51 and POLH (Roy 2012, Buisson 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 BRCA2 Val1779Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000561227	SCV000668578	likely benign	Hereditary cancer-predisposing syndrome	2024-03-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000561227	SCV000906727	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193174	SCV001361858	uncertain significance	not specified	2019-03-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5335G>A (p.Val1779Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5335G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561227	SCV003847171	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	RCV000082940	SCV003932740	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	BRCA2 c.5335G>A (p.Val1779Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245632 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5335G>A in individuals affected with Hereditary Breast and Ovarian Cancer. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000082940	SCV000115014	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing