rs61754796

Variant names:

• chr8-89971247-C-A
• rs61754796
• NM_002485.5:c.628G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89971247-C-A
• chr8-89971247-C-G
• chr8-89971247-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002485.5(NBN):​c.628G>T​(p.Val210Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,613,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. V210L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:10 O:2
• Conservation: PhyloP100: -0.408
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034131557).
• BP6: Variant 8-89971247-C-A is Benign according to our data. Variant chr8-89971247-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127014.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000784 (1145/1460924) while in subpopulation NFE AF = 0.000942 (1047/1111454). AF 95% confidence interval is 0.000894. There are 1 homozygotes in GnomAdExome4. There are 552 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.628G>T	p.Val210Phe	missense_variant	Exon 6 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.628G>T	p.Val210Phe	missense_variant	Exon 6 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000403 AC: 101 AN: 250916 AF XY: 0.000398

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000767

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000784 AC: 1145 AN: 1460924 Hom.: 1 Cov.: 30 AF XY: 0.000759 AC XY: 552 AN XY: 726798

African (AFR) AF: 0.0000898 AC: 3 AN: 33424

American (AMR) AF: 0.000179 AC: 8 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86244

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000942 AC: 1047 AN: 1111454

Other (OTH) AF: 0.00109 AC: 66 AN: 60336

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74450

African (AFR) AF: 0.000144 AC: 6 AN: 41562

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000696 Hom.: 1

Bravo AF: 0.000552

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:10 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4 Other:1

-

Harris Lab, University of Minnesota

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of breast, ovarian, and other cancers (PMID: 11325820, 16810201, 16770759, 17496786, 22491912, 24894818, 26315354, 26928227, 29522266, 34072463); In a breast cancer case-control analysis, this variant was not observed at a higher frequency in cases versus controls (PMID: 34072463); Published functional studies suggest a potential impact on DNA repair ability (PMID: 34072463); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19452044, 26787654, 16810201, 29522266, 32668560, 24894818, 11325820, 16770759, 24728327, 17496786, 20805886, 22491912, 24396275, 26928227, 26315354, 28873162, 29371908, 12353271, 26564480, 18606567, 29641532, 29844865, 31278556, 19804756, 34426522, 30306255, 31780696, 31874108, 35264596, 34326862, 34284872, 34072463, 37503171, 36346689) -

Jan 24, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NBN: BP4, BS1 -

Feb 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency Uncertain:3 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NBN c.628G>T (p.Val210Phe) missense change has a maximum subpopulation frequency of 0.076% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-90983475-C-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant is present 16x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2; https://whi.color.com/variant/8-90983475-C-A). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS2, BP4. -

Aug 29, 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. -

not specified Uncertain:2 Benign:1 Other:1

Sep 30, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NBN c.628G>T (p.Val210Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 267128 control chromosomes, predominantly at a frequency of 0.00077 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast And Ovarian Cancer (HBOC) Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.628G>T has been reported in the literature in individuals affected with cancer including HBOC and Acute Lymphoblastic Leukemia (e.g., Varon_2001, Mosor_2006, Steffen_2006, Mateju_2012, Damiola_2015, Ramus_2015, Bonache_2018, Dominguez-Valentin_2018, Hauke_2018, Dutil_2019, Zuntini_2021), but has also been reported in controls (e.g., Mateju_2012, Ramus_2015). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been observed by our lab (BRCA2 c.9027delT, p.His3010IlefsX18; Internal testing), providing supporting evidence for a benign role. The variant was also reported in 16 women older than age 70 years who have never had cancer (FLOSSIES database) providing further evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Zuntini_2021). The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 30306255, 12353271, 26564480, 29371908, 31780696, 29522266, 22491912, 31874108, 16810201, 32668560, 26315354, 16770759, 11325820, 26787654, 34072463). ClinVar contains an entry for this variant (Variation ID: 127014). Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 30, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NBN c.628G>T; p.Val210Phe variant (rs61754796) is reported in the literature in individuals with melanoma, acute lymphoblastic leukemia, breast or ovarian cancer (Dominguez-Valentin 2018, Mateju 2012, Meyer 2007, Mosor 2006, Ramus 2015, Steffen 2006, Varon 2001), but is also reported in controls (Mateju 2012, Offer 2010, Ramus 2015). This variant is also found in the general population with an overall allele frequency of 0.04% (115/282316 alleles) in the Genome Aggregation Database. This variant is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 127014). The valine at codon 210 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Mateju M et al. Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. Breast Cancer Res Treat. 2012 Jun;133(2):809-11. Meyer P et al. Molecular genetic analysis of NBS1 in German melanoma patients. Melanoma Res. 2007 Apr;17(2):109-16. Mosor M et al. Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia. 2006 Aug;20(8):1454-6. Offer SM et al. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One. 2010 Aug 18;5(8):e12260. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11). Steffen J et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer. 2006 Jul 15;119(2):472-5. Varon R et al. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 2001 May 1;61(9):3570-2. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Benign:2

Oct 09, 2018

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. -

Dec 27, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NBN-related disorder Uncertain:1

Jan 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NBN c.628G>T variant is predicted to result in the amino acid substitution p.Val210Phe. This variant has been reported in individuals with a history of acute lymphoblastic leukemia, breast cancer, and ovarian cancer (Mosor et al. 2006. PubMed ID: 16810201; Varon et al. 2001. PubMed ID: 11325820; Mateju et al. 2012. PubMed ID: 22491912; Steffen et al. 2006. PubMed ID: 16770759; Supplementary Table 4, Ramus et al. 2015. PubMed ID: 26315354; Zuntini et al. 2021. PubMed ID: 34072463), but has also been identified in cohorts of unaffected individuals (Supplementary Table 4, Ramus et al. 2015. PubMed ID: 26315354; Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127014/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NBN p.Val210Phe variant was identified in 4 of 3654 proband chromosomes (frequency: 0.001) from individuals or families with melanoma, breast cancer, Non-Hodgkin lymphomas, ALL (Meyer_2007, Damiola_2014, Cerosaletti_2002, Varon_2001). The variant was also identified in the following databases: dbSNP (ID: rs61754796) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae, GSLUC; classified as likely benign by Ambry Genetics), Clinvitae (classified as uncertain significance by ClinVar, Invitae; classified as likely benign by ClinVar), and the Zhejiang Colon Cancer Database. The variant was not identified in Cosmic or LOVD 3.0, databases. The variant was identified in 116 of 276770 chromosomes at a frequency of 0.0004 in the following populations: African in 3 of 24004 chromosomes (freq. 0.000125), “other” in 3 of 6450 chromosomes (freq. 0.00046), Latino in 4 of 34354 chromosomes (freq. 0.000116), European in 97 of 126420 chromosomes (freq. 0.00076), Finnish in 5 of 25764 chromosomes (freq. 0.0002), and South Asian in 4 of 30782 chromosomes (freq. 0.00013), increasing the likelihood this could be a low frequency benign variant in certain populations (Genome Aggregation Consortium Feb 27, 2017). The p.Val210 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. The variant is located with the Nibrin functional domain. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer Benign:1

Feb 27, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.037	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L;.;.;.
PhyloP100		-0.41
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N;N;N;D
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;.
Polyphen		0.21	B;.;.;.
Vest4		0.58
MVP		0.80
MPC		0.094
ClinPred		0.041	T
GERP RS		-1.9
Varity_R		0.12
gMVP		0.66
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61754796; hg19: chr8-90983475;