Submissions for variant NM_000059.4(BRCA2):c.6099A>G (p.Ile2033Met)

dbSNP: rs80358848

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164759	SCV000215435	uncertain significance	Hereditary cancer-predisposing syndrome	2014-07-11	criteria provided, single submitter	clinical testing	The p.I2033M variant (also known as c.6099A>G or 6327A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6099. The isoleucine at codon 2033 is replaced by methionine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs80358848. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.006% (greater than 42000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.I2033M remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309364	SCV001498860	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2033 of the BRCA2 protein (p.Ile2033Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18284688). ClinVar contains an entry for this variant (Variation ID: 52011). 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. 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	RCV000164759	SCV001735338	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 2033 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 hereditary cancer in the literature. This variant has not been identified 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164759	SCV003850927	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).
PreventionGenetics, part of Exact Sciences	RCV004537199	SCV004103060	uncertain significance	BRCA2-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	The BRCA2 c.6099A>G variant is predicted to result in the amino acid substitution p.Ile2033Met. This variant was reported in at least one individual from a cohort of patients with early-onset breast cancer (Lee et al. 2008. PubMed ID: 18284688). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. In ClinVar, this variant is classified as a variant of uncertain significance and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/52011/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV004721252	SCV005327576	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	Not observed in any cases but was observed in the unaffected controls in a breast cancer study (PMID: 30287823); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 6327A>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 30287823, 36243179)
All of Us Research Program, National Institutes of Health	RCV004803868	SCV005424519	uncertain significance	BRCA2-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 2033 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 hereditary cancer in the literature. This variant has not been identified 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113531	SCV000146767	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing