ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.798G>A (p.Pro266=) (rs368786672)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418518 SCV000521773 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000459383 SCV000553122 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-10-27 criteria provided, single submitter clinical testing This sequence change affects codon 266 of the NBN mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NBN protein. This variant is present in population databases (rs368786672, ExAC 0.01%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 382019). 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.
Ambry Genetics RCV000566951 SCV000662672 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing The c.798G>A variant (also known as p.P266P), located in coding exon 7, results from a G to A substitution at nucleotide position 798 of the NBN gene. This nucleotide substitution does not change the amino acid at codon 266. This alteration was reported with an allele frequency of 0.001 in 12,490 Japanese controls, and was not observed in 53 male breast cancer cases (Momozawa Y et al Nat Commun 2018 10;9(1):4083). This nucleotide position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000566951 SCV000690741 likely benign Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357322 SCV001552763 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Pro266= variant was not identified in the literature. The variant was identified in dbSNP (rs368786672) as “with other allele”, ClinVar (classified as likely benign by GeneDx and Ambry Genetics; and as uncertain significance by Invitae and Ambry Genetics) and LOVD 3.0 (observed 2x). The variant was identified in control databases in 3 of 246,064 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111,586 chromosomes (freq: 0.000009) and South Asian in 2 of 30,780 chromosomes (freq: 0.00007), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Pro266= variant is not expected to have clinical significance because it does not result in a change of amino acid and it occurs at a non-conserved nucleotide outside of the splicing consensus sequence. However, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the introduction of a cryptic splice site; this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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