ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.456G>A (p.Met152Ile) (rs201816949)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115795 SCV000186697 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115795 SCV000537561 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000509203 SCV000344520 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515395 SCV000611489 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000509203 SCV000149704 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted NBN c.456G>A at the cDNA level, p.Met152Ile (M152I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed in at least two individuals with breast and/or ovarian cancer, one individual with colon cancer and one individual with a Lynch syndrome associated cancer and/or colon polyps (Ramus 2015, Yurgelun 2015, Pearlman 2016, Cock-Rada 2017). NBN Met152Ile was observed at an allele frequency of 0.02% (28/126,568) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in n the BRCT1 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 Met152Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000509203 SCV000607210 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000781635 SCV000919845 uncertain significance not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: NBN c.456G>A (p.Met152Ile) results in a conservative amino acid change located in the 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 0.00012 in 276952 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer (0.00012 vs 0.00013), allowing no conclusion about variant significance. c.456G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer, or colon cancer and/or polyps (Ramus 2015, Yurgelun 2015, Pearlman 2016, Cock-Rada 2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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.
Invitae RCV000197783 SCV000254776 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 152 of the NBN protein (p.Met152Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs201816949, ExAC 0.02%). This variant has been reported in an individual with Lynch syndrome-associated cancer and/or colon polyps (PMID: 25980754), and an individual with serous ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 127872). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
True Health Diagnostics RCV000115795 SCV000886693 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 no assertion criteria provided clinical testing

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