NM_002485.5:c.1809C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002485.5(NBN):c.1809C>A(p.Phe603Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,612,950 control chromosomes in the GnomAD database, including 2 homozygotes. 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).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -0.626

Variant links:

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]

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044291615).

BP6

Variant 8-89953280-G-T is Benign according to our data. Variant chr8-89953280-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185174.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=5, Uncertain_significance=1}. Variant chr8-89953280-G-T is described in Lovd as [Likely_benign]. Variant chr8-89953280-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152192) while in subpopulation EAS AF= 0.00501 (26/5186). AF 95% confidence interval is 0.00351. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1809C>A	p.Phe603Leu	missense_variant	Exon 11 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1809C>A	p.Phe603Leu	missense_variant	Exon 11 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00500

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000383

AC:

AN:

250792

Hom.:

AF XY:

0.000347

AC XY:

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00495

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1460758

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00391

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000177

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00501

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000326

Hom.:

Bravo

AF:

0.000246

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:1Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Jun 25, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jan 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24349281, 25712764, 26315354, 23555315, 30942098, 32668560) -

Jun 05, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NBN c.1809C>A (p.Phe603Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 40/128334 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.004161 (36/8652). This frequency is about 33 times the estimated maximal expected allele frequency of a pathogenic NBN variant (0.000125), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. his variant was reported in two studies in non-BRCA1/2 Korean patients with high-risk breast cancer and European populations with high risk of ovarian cancer, but was also observed in controls (Kim_FC_2015, Ramus_NBN1_JNCI_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Dec 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 02, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NBN p.Phe603Leu variant was identified in 7 of 7106 proband chromosomes (frequency: 0.001) from individuals or families with hepatocellular carcinoma, breast or ovarian cancer (Kim 2015, Ramus 2015, Wang 2013). The variant was also identified in dbSNP (ID: rs192236678) as "With Likely benign allele ", ClinVar (classified as benign by Invitae, Integrated Genetics/Laboratory Corporation of America; as likely bening by Ambry Genetics, GeneDx, and two clinical laboratories), and in LOVD 3.0 (1x) databases. The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 102 of 276468 chromosomes 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: East Asian in 98 of 18856 chromosomes (freq: 0.005), and South Asian in 4 of 30768 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, and Finnish populations. The p.Phe603 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Hereditary breast ovarian cancer syndrome

Benign:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.4

DANN

Benign

0.34

DEOGEN2

Benign

0.054

T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.38

T;T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.58

N;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.29

N;N;.

REVEL

Benign

0.0060

Sift

Benign

0.57

T;T;.

Sift4G

Benign

0.66

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.047

MutPred

0.20

Gain of loop (P = 3e-04);.;.;

MVP

0.38

MPC

0.078

ClinPred

0.0051

GERP RS

-11

Varity_R

0.016

gMVP

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over