Submissions for variant NM_002485.5(NBN):c.1363A>G (p.Ile455Val)

dbSNP: rs1554559041

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000772506	SCV001171420	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-06	criteria provided, single submitter	clinical testing	The p.I455V variant (also known as c.1363A>G), located in coding exon 10 of the NBN gene, results from an A to G substitution at nucleotide position 1363. The isoleucine at codon 455 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236893	SCV001409634	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 455 of the NBN protein (p.Ile455Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 628170). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Genome-Nilou Lab	RCV001236893	SCV002044648	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004997278	SCV005623876	uncertain significance	not provided	2024-03-26	criteria provided, single submitter	clinical testing	The NBN c.1363A>G (p.Ile455Val) variant has been observed in the published literature in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN) as well as a reportedly healthy individual (PMID: 31206626 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056516	SCV005726825	uncertain significance	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1363A>G (p.Ile455Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251230 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1363A>G has been reported in the literature in individuals affected with breast cancer without cosegregation information (Dorling_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33471991). ClinVar contains an entry for this variant (Variation ID: 628170). Based on the evidence outlined above, the variant was classified as uncertain significance.