rs104895032

chr8-89955418-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002485.5(NBN):c.1262T>C(p.Leu421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,613,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L421L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:15 O:1
• Conservation: PhyloP100: -0.00200

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=0.0078063905).
• BP6: Variant 8-89955418-A-G is Benign according to our data. Variant chr8-89955418-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=7, not_provided=1, Benign=2}. Variant chr8-89955418-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.1262T>C	p.Leu421Ser	missense_variant	10/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.1262T>C	p.Leu421Ser	missense_variant	10/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251376 Hom.: 1 AF XY: 0.000397 AC XY: 54 AN XY: 135856

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000315 AC: 460 AN: 1461652 Hom.: 1 Cov.: 32 AF XY: 0.000308 AC XY: 224 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74436

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 08, 2017	- -
not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2021	This variant is associated with the following publications: (PMID: 25980754, 26315354, 23555315, 20805886, 28135145, 28873162, 28726808, 30374176, 31278556) -

Microcephaly, normal intelligence and immunodeficiency Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneID Lab - Advanced Molecular Diagnostics	Sep 07, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 10, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2021	Variant summary: NBN c.1262T>C (p.Leu421Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 260122 control chromosomes in the gnomAD database, including 1 homozygote. The variant was also reported in 7 European American women older than age 70 years who have never had cancer. This data provide supporting evidence for a benign role. c.1262T>C has been reported in the literature in individuals affected with CVID, OvC, HBOC, Lynch syndrome and PDAC (e.g. Offer_2010, Ramus_2015, Tung_2015, Yurgelun_2015, 2017, Chaffee_2018, Dorling_2021) but it was also reported in multiple controls (Offer_2010, Ramus_2015, Dorling_2021). Additionally, evidence of non co-segregation with disease was provided through the study of a large family affected with different types of cancer including breast cancer (Tsai_2019), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and eight ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely 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

May 23, 2017

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The NBN p.Leu421Ser variant was identified in 5 of 11992 proband chromosomes (frequency: 0.0004) from individuals or families with antibody deficiency syndromes IgAD or CVID, ovarian cancer or Lynch syndrome and was present in 3 of 8746 control chromosomes (frequency: 0.0005) from healthy individuals (Offer 2010, Ramus 2015, Yurgelun 2015, Yurgelun 2017). The variant was also found in Genome-Wide testing of putative functional exonic variants with relative risk 1.224 and P=0.87 (Haiman 2013). The variant was identified in dbSNP (ID: rs104895032) as "With other allele", and in ClinVar (classified as benign by Invitae; as uncertain significance by eight submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 105 of 277090 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24016 chromosomes (freq: 0.0003), Other in 3 of 6458 chromosomes (freq: 0.0005), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 44 of 126620 chromosomes (freq: 0.0004), Ashkenazi Jewish in 43 of 10152 chromosomes (freq: 0.004), Finnish in 8 of 25790 chromosomes (freq: 0.0003), while the variant was not observed in the East Asian, and South Asian populations. The p.Leu421 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

May 29, 2018

The NBN variant designated as NM_002485.4: c.1262T>C (p.Leu421Ser) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yields a likelihood ratio of 1.88 to 1 that the allele is causing cancer in the family (Thompson et al, 2003, PMID:2900794, Damiola et al, 2014, PMID:24894818). However, this variant is found in approximately 1 out of 120 individuals of Ashkenazi Jewish ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic NBN variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 127009) and has been classified as benign by another clinical laboratory. Computer software programs also predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter NBN function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.2
Dann	Benign	0.60
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.040
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.096	T;D
Polyphen		0.38	B;.
Vest4		0.25
MVP		0.44
MPC		0.098
ClinPred		0.012	T
GERP RS		-0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.17

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: rs104895032; hg19: chr8-90967646;