ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5553C>G (p.Ile1851Met)

gnomAD frequency: 0.00001  dbSNP: rs573514896
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215045 SCV000275519 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-31 criteria provided, single submitter clinical testing The p.I1851M variant (also known as c.5553C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5553. The isoleucine at codon 1851 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Fackenthal JD et al. Int J Cancer, 2012 Sep;131:1114-23). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587837 SCV000694880 uncertain significance not provided 2016-03-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5553C>G (p.Ile1851Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. The variant of interest has been observed in a large, broad control population, ExAC, in 1/120654 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant is located in one of the BRCA repeats that is critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment (IPR002093). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001359833 SCV001555719 uncertain significance Hereditary breast ovarian cancer syndrome 2025-02-04 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 1851 of the BRCA2 protein (p.Ile1851Met). This variant is present in population databases (rs573514896, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 22034289). ClinVar contains an entry for this variant (Variation ID: 231617). 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.
GeneDx RCV000587837 SCV002820866 uncertain significance not provided 2022-07-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Fackenthal et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5781C>G; This variant is associated with the following publications: (PMID: 22034289, 9002670, 22193408)
University of Washington Department of Laboratory Medicine, University of Washington RCV000215045 SCV003848910 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).
Sharing Clinical Reports Project (SCRP) RCV000239014 SCV000297539 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2012-09-21 no assertion criteria provided clinical testing

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