Submissions for variant NM_000059.4(BRCA2):c.4090A>G (p.Ile1364Val)

dbSNP: rs56248502

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130224	SCV000185064	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.I1364V variant (also known as c.4090A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4090. The isoleucine at codon 1364 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in an individual diagnosed with breast cancer (Bakkach J et al. BMC Cancer, 2020 Sep;20:859). 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.
Counsyl	RCV000410854	SCV000489410	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-03	criteria provided, single submitter	clinical testing
Invitae	RCV000557623	SCV000635334	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1364 of the BRCA2 protein (p.Ile1364Val). This variant is present in population databases (rs56248502, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 32894085). ClinVar contains an entry for this variant (Variation ID: 141629). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587668	SCV000694742	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4090A>G (p.Ile1364Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120860 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587668	SCV000889042	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170463	SCV001333043	uncertain significance	Breast and/or ovarian cancer	2018-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000587668	SCV001792785	uncertain significance	not provided	2020-11-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer who also harbors a pathogenic BRCA1 variant (Bakkach 2020); Also known as 4318A>G; This variant is associated with the following publications: (PMID: 32894085, 23697973)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130224	SCV003848671	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	RCV000410854	SCV004845270	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1364 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 an individual with early-onset breast cancer, who also carried a pathogenic variant in BRCA1 that could explain the observed phenotype (PMID:32894085). This variant has been identified in 4/280752 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.