ClinVar Miner

Submissions for variant NM_001024688.2(NBN):c.1237_1238delinsA (p.Pro413fs) (rs764884516)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166379 SCV000217171 pathogenic Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000482780 SCV000569547 pathogenic not provided 2016-03-07 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted NBN c.1483_1484delCCinsA at the cDNA level and p.Pro495MetfsX34 (P495MfsX34) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is ACAA[CC][A]TGCT. The variant causes a frameshift which changes a Proline to a Methionine at codon 495, and creates a premature stop codon at position 34 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. NBN, also known as NBS1, has only recently been described in association with cancer predisposition and the risks are not well understood. Most of the studies evaluating cancer risk associated with NBN have analyzed one pathogenic frameshift variant, 657del5, and we cannot determine whether the risks conferred by the current result would be similar. NBN 657del5 has been significantly associated with breast cancer (OR=3.1), with higher odds at earlier ages of diagnosis (OR=4.2 for women diagnosed before 50 years of age) (Steffen 2006a). The association of this pathogenic variant with breast cancer, however, has not been observed in all populations (Buslov 2005, di Masi 2008, Mateju 2012). NBN 657del5 has also been observed in a higher frequency in cases vs. controls for melanoma (OR=6.4) and non-Hodgkin lymphoma (OR=5.9), particularly gastrointestinal lymphoma, albeit with wide confidence intervals (Steffen 2004, 2006b). Studies of missense NBN variants have shown ambiguous results with respect to cancer risk (di Masi 2008, He 2014). Two pathogenic variants (one affecting each allele) in the NBN gene cause a rare disorder called Nijmegen breakage syndrome (NBS). This condition is characterized by growth retardation, immunodeficiency, microcephaly, hypersensitivity to radiation, and increased risk for lymphoma and leukemia (Kanka 2007, Steffen 2004). If both parents carry an NBN pathogenic variant, the risk to have a child with NBS is 25% for each pregnancy.
Invitae RCV000636722 SCV000758162 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro495Metfs*34) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs764884516, 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: 186736). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.

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