ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.683T>G (p.Ile228Arg) (rs777460725)

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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 RCV000165931 SCV000216687 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000198580 SCV000254779 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with arginine at codon 228 of the NBN protein (p.Ile228Arg). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and arginine. This variant is present in population databases (ExAC 0.02%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 186350). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000587016 SCV000279987 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing This variant is denoted NBN c.683T>G at the cDNA level, p.Ile228Arg (I228R) at the protein level, and results in the change of an Isoleucine to an Arginine (ATA>AGA). This variant has been identified in at least one individual with a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). NBN Ile228Arg was observed at an allele frequency of 0.01% (3/25740) in individuals of European (Finnish) ancestry in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Ile228Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165931 SCV000685815 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855653 SCV000697979 uncertain significance not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: NBN c.683T>G (p.Ile228Arg) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276394 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (6.5e-05 vs 0.0025), allowing no conclusion about variant significance. The variant, c.683T>G, has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). These report does not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764785 SCV000895929 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing

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