Submissions for variant NM_000059.4(BRCA2):c.6688A>G (p.Ile2230Val)

dbSNP: rs587779366

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586574	SCV000108634	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer and absent in controls in a breast cancer case-control study (PMID: 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 6916A>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 31911673, 31853058, 33471991)
Ambry Genetics	RCV000130830	SCV000185727	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-24	criteria provided, single submitter	clinical testing	The p.I2230V variant (also known as c.6688A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6688. The isoleucine at codon 2230 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474506	SCV000549757	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-25	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 2230 of the BRCA2 protein (p.Ile2230Val). 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: 89052). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130830	SCV000683796	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2230 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 detected in a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008493). This variant has been identified in 1/251182 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586574	SCV000694985	uncertain significance	not provided	2016-01-19	criteria provided, single submitter	clinical testing	Variant summary: The c.6688A>G in BRCA2 gene is a missense variant involves a conserved nucleotide and 3/4 in silico tools predict benign outcome. This variant is not present in the control population dataset of ExAC, suggesting this variant is not a common polymorphism. The variant is not reported in the literature, however, was found to co-occur with a deleterious variant, c.2457delC in BRCA1 gene in individual referred for genetic testing (internal LCA data). In addition, the variant was classified as VUS by several reputable clinical laboratories/diagnostic centers. Taken together, the variant was classified as Variant of Uncertain until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586574	SCV001133871	uncertain significance	not provided	2018-11-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130830	SCV003847365	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	RCV003997059	SCV004844295	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2230 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 detected in a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008493). This variant has been identified in 1/251182 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.