ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1465C>G (p.Leu489Val) (rs143948240)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164141 SCV000214757 likely benign Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000197233 SCV000254764 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 489 of the NBN protein (p.Leu489Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs143948240, ExAC 0.005%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 184816). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color Health, Inc RCV000164141 SCV000685722 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-20 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 489 of the NBN protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 5/250592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000197233 SCV000799572 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-04-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354892 SCV001549611 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Leu489Val variant was identified in 1 of 2116 proband chromosomes (frequency: 0.0005) from individuals or families with colorectal cancer (Yurgelun 2017). The variant was also identified in dbSNP (ID: rs143948240) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, Color, and Counsyl). The variant was not identified in LOVD 3.0 database. The variant was identified in 3 of 245400 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the Ashkenazi Jewish population in 3 of 9836 chromosomes (freq: 0.0003), but not in the African, Other, Latino, European, East Asian, European Finnish, or South Asian populations. The p.Leu489 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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