rs61754796
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
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. 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).
Frequency
Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00078 ( 1 hom. )
Consequence
NBN
NM_002485.5 missense
NM_002485.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: -0.408
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -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 id is 127014.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=2, Uncertain_significance=10}. Variant chr8-89971247-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 552 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NBN | NM_002485.5 | c.628G>T | p.Val210Phe | missense_variant | 6/16 | ENST00000265433.8 | NP_002476.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NBN | ENST00000265433.8 | c.628G>T | p.Val210Phe | missense_variant | 6/16 | 1 | NM_002485.5 | ENSP00000265433 | P1 |
Frequencies
GnomAD3 genomes 0.000480 AC: 73AN: 152156Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000403 AC: 101AN: 250916Hom.: 0 AF XY: 0.000398 AC XY: 54AN XY: 135684
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GnomAD4 exome AF: 0.000784 AC: 1145AN: 1460924Hom.: 1 Cov.: 30 AF XY: 0.000759 AC XY: 552AN XY: 726798
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GnomAD4 genome 0.000486 AC: 74AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:9Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:4Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2022 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| not provided, no classification provided | literature only | Harris Lab, University of Minnesota | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); 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) - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 06, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | NBN: BP4, BS1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Microcephaly, normal intelligence and immunodeficiency Uncertain:4Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 29, 2017 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 12, 2022 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 19, 2021 | 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. - |
not specified Uncertain:2Benign:1Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 30, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2023 | 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). Multiple ClinVar submitters (evaluation after 2014) have reported the variant; eleven submitters cited the variant as uncertain significance and six submitters cited it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 25, 2019 | 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. - |
Hereditary cancer-predisposing syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 27, 2021 | - - |
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 | - - |
NBN-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 22, 2024 | 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
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
N;N;N;D
REVEL
Benign
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;.
Polyphen
B;.;.;.
Vest4
MVP
MPC
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at