rs863224714

Positions:

• chr8-89953605-G-A
• chr8-89953605-G-C
• chr8-89953605-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5 BP4

The NM_002485.5(NBN):​c.1484C>T​(p.Pro495Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P495S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 4.92

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-89953605-GG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2789816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.1484C>T	p.Pro495Leu	missense_variant	11/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.1484C>T	p.Pro495Leu	missense_variant	11/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461226 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000430 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 495 of the NBN protein (p.Pro495Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 216564). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 03, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2022	The frequency of this variant in the general population, 0.000032 (1/31372 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in an individual with colon cancer (PMID: 27978560 (2016)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer (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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 26, 2023	The c.1484C>T (p.P495L) alteration is located in exon 11 (coding exon 11) of the NBN gene. This alteration results from a C to T substitution at nucleotide position 1484, causing the proline (P) at amino acid position 495 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Apr 14, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 24, 2022

Variant summary: NBN c.1484C>T (p.Pro495Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250652 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1484C>T has been reported in the literature as a VUS in at-least one mismatch repair (MMR) proficient individual from a cohort undergoing multigene panel testing for early onset colorectal cancer (example, Pearlman_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome or NBN-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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. -

Aplastic anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.097
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.94	P;.
Vest4		0.33
MVP		0.80
MPC		0.32
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224714; hg19: chr8-90965833;