8-89946211-A-G

Position:

chr8-89946211-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002485.5(NBN):c.1999T>C(p.Ser667Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000988 in 1,599,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 1.04

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:

NBN (HGNC:):

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03158495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.1999T>C	p.Ser667Pro	missense_variant	13/16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.1999T>C	p.Ser667Pro	missense_variant	13/16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000883

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251130

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000919

AC:

133

AN:

1447134

Hom.:

Cov.:

AF XY:

0.0000874

AC XY:

AN XY:

720786

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.000313

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:

0.000101

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000164

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000249

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 667 of the NBN protein (p.Ser667Pro). This variant is present in population databases (rs587780091, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, ovarian cancer, and/or prostate cancer (PMID: 26315354, 29596542, 29659569, 30256826, 31206626, 35245693). ClinVar contains an entry for this variant (Variation ID: 127863). 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 proline 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. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian, colon, and prostate cancer (PMID: 26315354, 29596542, 30256826, 29659569); This variant is associated with the following publications: (PMID: 30256826, 26315354, 29596542, 29659569, 32936981, 33471991, 36243179, 31206626, 36346689, 35245693) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2024	The NBN c.1999T>C (p.Ser667Pro) variant has been reported in the published literature in individuals with breast cancer (PMID: 31206626 (2019), 32936981 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)), ovarian cancer (PMID: 26315354 (2015)), colorectal cancer (PMID: 29596542 (2018)), prostate cancer (PMID: 29659569 (2018)), other unspecified cancer types (PMID: 36346689 (2023)), and an individual that met clinical criteria for Lynch Syndrome (PMID: 30256826 (2018)). Additionally, this variant has seen in reportedly healthy individuals (PMID: 26315354 (2015), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/), 36243179 (2022)). The frequency of this variant in the general population, 0.00017 (6/35408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 22, 2024	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	curation	Sema4, Sema4	Dec 23, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 05, 2023

Variant summary: NBN c.1999T>C (p.Ser667Pro) 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 5.6e-05 in 251130 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (5.6e-05 vs 0.0025), allowing no conclusion about variant significance. c.1999T>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals with cancers such as breast and ovarian (e.g., Ramus_2015, Weitzel_2019, Castillo-Guardiola_2022), colorectal (e.g., Hampel_2018, Martin-Morales_2018), and prostate (e.g., Paulo_2018) and in unaffected controls (e.g., Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome and/or NBN-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29596542, 26315354, 31206626, 35245693, 30256826, 29659569, 36346689). Twelve submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n = 10; likely benign, n = 2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

- -

Aplastic anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 11, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

NBN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The NBN c.1999T>C variant is predicted to result in the amino acid substitution p.Ser667Pro. This variant has been reported in individuals with ovarian cancer and controls at approximately equal frequency (Ramus et al. 2015. PubMed ID: 26315354. Table S4). It has also been reported in individuals with colorectal cancer and interpreted as uncertain significance ( eTable 2, Hampel et al. 2018. PubMed ID: 29596542; Martin-Morales et al. 2018. PubMed ID: 30256826). This variant was also observed in the controls cohort at a carrier frequency of 0.001% but not in the cases cohort in a large study of hereditary cancer variants (Table S2, Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127863/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.8

DANN

Benign

0.42

DEOGEN2

Benign

0.074

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.019

Sift

Benign

0.54

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0010

B;.

Vest4

0.044

MutPred

0.39

Gain of loop (P = 0.0013);.;

MVP

0.65

MPC

0.084

ClinPred

0.025

GERP RS

0.20

Varity_R

0.052

gMVP

0.12

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