ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8113A>G (p.Ser2705Gly) (rs756105620)

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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 RCV000510067 SCV000607802 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000510067 SCV000906571 likely benign Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000586599 SCV000329140 uncertain significance not provided 2017-04-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8113A>G at the cDNA level, p.Ser2705Gly (S2705G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). Using alternate nomenclature, this variant would be defined as BRCA2 8341A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser2705Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2705Gly occurs at a position that is not conserved and is within the DNA binding domain (Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser2705Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586599 SCV000695128 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8113A>G (p.Ser2705Gly) variant located in the Nucleic acid-binding, OB fold domain (via InterPro) causes a missense change involving the alteration of a non-conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121378, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333 (0.0007503). A reputable database cites the variant with a classification of "UV," which 1 individual was indicated to carry another potentially pathogenic BRCA1 variant, c.4066C>T (p.Gln1356X). In addition, a clinical diagnostic laboratory cites the variant as "uncertain significance." The variant of interest has not been, to our knowledge, reported in affected individuals via publications. Therefore, until additional information becomes available (ie, clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000530767 SCV000635639 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 2705 of the BRCA2 protein (p.Ser2705Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs756105620, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 279706). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000335958 SCV000600785 uncertain significance not specified 2017-01-17 criteria provided, single submitter clinical testing

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