Submissions for variant NM_000059.4(BRCA2):c.8098A>C (p.Ile2700Leu)

gnomAD frequency: 0.00001  dbSNP: rs80359053

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195382	SCV000073434	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-02	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 2700 of the BRCA2 protein (p.Ile2700Leu). This variant is present in population databases (rs80359053, gnomAD 0.007%). 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: 52504). 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.
Ambry Genetics	RCV000130878	SCV000185783	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The p.I2700L variant (also known as c.8098A>C), located in coding exon 17 of the BRCA2 gene, results from an A to C substitution at nucleotide position 8098. The isoleucine at codon 2700 is replaced by leucine, an amino acid with highly similar properties. 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.
GeneDx	RCV000588136	SCV000210461	uncertain significance	not provided	2016-01-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8098A>C at the cDNA level, p.Ile2700Leu (I2700L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>CTA). This variant, also known as 8326A>C using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2700Leu 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 Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2700Leu occurs at a position that is not conserved and is located within the DNA binding domain (Borg 2010). 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 Ile2700Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130878	SCV000689096	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 2700 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/251356 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	RCV000588136	SCV000695126	uncertain significance	not provided	2016-02-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000077427	SCV000785144	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000077427	SCV004018686	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-23	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588136	SCV004220588	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251356 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with a personal or family history of hereditary breast and/or ovarian cancer (HBOC) (PMID: 31853058 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004803906	SCV004845596	uncertain significance	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 2700 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/251356 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)	RCV000077427	SCV000109225	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-07-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077427	SCV000147273	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing