rs182756889

chr8-89978299-G-Achr8-89978299-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002485.5(NBN):c.505C>T(p.Arg169Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000061 in 1,589,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:1
• Conservation: PhyloP100: 0.214

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06714395).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152158) while in subpopulation EAS AF= 0.00193 (10/5184). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.505C>T	p.Arg169Cys	missense_variant	5/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.505C>T	p.Arg169Cys	missense_variant	5/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251246 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135824

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000550 AC: 79 AN: 1437172 Hom.: 0 Cov.: 28 AF XY: 0.0000558 AC XY: 40 AN XY: 716378

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000836

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000340

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74400

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000519 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the NBN protein (p.Arg169Cys). This variant is present in population databases (rs182756889, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501, 25712764, 25980754). ClinVar contains an entry for this variant (Variation ID: 127873). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 09, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, and other cancers, but also in healthy control groups and in an individual with breast cancer and a co-occurring truncating BRCA1 variant (Kim et al., 2015; Maxwell et al., 2015; Yurgelun et al., 2015; Hauke et al., 2018; Momozawa et al., 2018; Wang et al., 2019; Fujita et al., 2020; Kwong et al., 2020; Mizukami et al., 2020); This variant is associated with the following publications: (PMID: 25712764, 25980754, 25503501, 29522266, 33309985, 33800431, 36632296, 24894818, 25186627, 31666926, 30287823, 30982232, 32068069, 32980694, 32566746, 36427680) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 07, 2023	The frequency of this variant in the general population, 0.00065 (13/19954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25503501 (2015), 25712764 (2015)), familial breast and/or ovarian cancer (PMID: 25980754 (2019), 32068069 (2020)), suspected Lynch syndrome (PMID: 25980754 (2015)), biliary tract carcinoma (PMID: 31666926 (2019)), pancreatic cancer (PMID: 32980694 (2020)), and colorectal cancer (PMID: 33309985 (2020)). This variant has also been reported in unaffected individuals (PMID: 32980694 (2020), 33309985 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 12, 2021

Variant summary: NBN c.505C>T (p.Arg169Cys) 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 allele was found at a frequency of 0.00023 in 298708 control chromosomes (gnomAD and Momozawa_2018. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is benign. c.505C>T has been reported in the literature in individuals affected with various types of cancers including but not limiting to breast and/or ovarian cancer, colorectal cancer, nasopharyngeal cancer and gall bladder cancer (example: Fujita_2020, Kwong_2020, Momozawa_2018, Terashima_2019, Wang_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

NBN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

The NBN c.505C>T variant is predicted to result in the amino acid substitution p.Arg169Cys. This variant has been observed within individuals with early-onset breast cancer and suspected Lynch syndrome (Maxwell et al. 2015. PubMed ID: 25503501, Supplementary Table 1; Yurgelun et al. 2015. PubMed ID: 25980754, Supplementary Table 2). However, this variant has also been reported in control cohorts (Supplemental Data 2, Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90990527-G-A) and in ClinVar has conflicting interpretations ranging from 'likely benign' to a ‘variant of uncertain significance’ (https://www.ncbi.nlm.nih.gov/clinvar/variation/127873/). While we suspect that this variant is likely benign, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.37	T;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.89	D;T;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.39	N;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.19	T;T;T;T
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		0.16	B;.;.;.
Vest4		0.30
MVP		0.66
MPC		0.092
ClinPred		0.039	T
GERP RS		-2.5
Varity_R		0.047
gMVP		0.72

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: rs182756889; hg19: chr8-90990527; COSMIC: COSV55377096; COSMIC: COSV55377096;