ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115795 SCV000186697 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000197783 SCV000254776 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-12-30 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 individuals with Lynch syndrome-associated cancer and/or colon polyps (PMID: 25980754, 28135145), 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000509203 SCV000344520 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing
Color RCV000115795 SCV000537561 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-07 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
Integrated Genetics/Laboratory Corporation of America RCV000781635 SCV000919845 uncertain significance not specified 2019-11-01 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 251220 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, one database reported this variant was found in seven women older than age 70 years who have never had cancer. 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, Bonache_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another BRCA2 pathogenic variant has been internally reported (c.5864C>A, p.Ser1955X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Clinical Services Laboratory,Illumina RCV000197783 SCV001324897 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-06-06 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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.
True Health Diagnostics RCV000115795 SCV000886693 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 no assertion criteria provided clinical testing

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