Submissions for variant NM_002485.5(NBN):c.940G>A (p.Val314Met)

gnomAD frequency: 0.00002  dbSNP: rs529845940

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130348	SCV000185199	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-13	criteria provided, single submitter	clinical testing	The p.V314M variant (also known as c.940G>A), located in coding exon 8 of the NBN gene, results from a G to A substitution at nucleotide position 940. The valine at codon 314 is replaced by methionine, 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 deleterious 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	RCV000464039	SCV000553111	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 314 of the NBN protein (p.Val314Met). This variant is present in population databases (rs529845940, gnomAD 0.006%). 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: 141727). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781636	SCV000919846	uncertain significance	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: NBN c.940G>A (p.Val314Met) alters a conserved nucleotide that results in a conservative amino acid change located in the Nibrin second BRCT domain (IPR032429) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 245998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (2.8e-05 vs 2.50E-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.940G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrences with the pathogenic variant MUTYH c.536A>G (p.Y179C) was found in an internal specimen. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000464039	SCV001761654	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-07-15	criteria provided, single submitter	clinical testing	The NBN c.940G>A (p.Val314Met) missense change has a maximum subpopulation frequency of 0.0079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-90976692-C-T). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome or breast cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Genome-Nilou Lab	RCV000464039	SCV002044744	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV002469021	SCV002765178	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24662767, 25186949, 24894818)
Baylor Genetics	RCV003467142	SCV004199628	uncertain significance	Aplastic anemia	2024-02-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002469021	SCV004222150	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000079 (9/113574 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected study control participants (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). 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.
Natera, Inc.	RCV000464039	SCV001460726	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing