Submissions for variant NM_002485.5(NBN):c.456G>A (p.Met152Ile)

gnomAD frequency: 0.00014  dbSNP: rs201816949

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000509203	SCV000149704	uncertain significance	not provided	2023-12-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with a personal or family history including breast, ovarian, colorectal, and other cancers (PMID: 23555315, 25980754, 26315354, 27978560, 28135145, 28528518); This variant is associated with the following publications: (PMID: 25980754, 26787654, 26315354, 23555315, 27978560, 28528518, 28135145, 30306255, 31874108, 33095795, 24894818, 34326862, 36346689, 37503171)
Ambry Genetics	RCV000115795	SCV000186697	likely benign	Hereditary cancer-predisposing syndrome	2020-06-05	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197783	SCV000254776	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-12-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000509203	SCV000344520	uncertain significance	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515395	SCV000611489	uncertain significance	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781635	SCV000919845	likely benign	not specified	2025-03-24	criteria provided, single submitter	clinical testing	Variant summary: NBN c.456G>A (p.Met152Ile) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251220 control chromosomes, predominantly at a frequency of 0.00019 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 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013). In addition, one database reported this variant was found in seven women older than age 70 years who have never had cancer (FLOSSIES database). c.456G>A has been reported in the literature in individuals affected with breast and ovarian cancer, primary ovarian insufficiency, colon cancer and/or polyps, or prostate cancer (Ramus_2015, Yurgelun_2015, Pearlman_2016, Cock-Rada_2017, Bonache_2018, Franca_2020, Mateo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Escherich_2024). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 36346689, 30306255, 28528518, 38446568, 33095795, 31874108, 27978560, 26315354, 25980754). ClinVar contains an entry for this variant (Variation ID: 127872). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000197783	SCV001324897	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-06-06	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000509203	SCV001470031	uncertain significance	not provided	2024-04-19	criteria provided, single submitter	clinical testing	The NBN c.456G>A (p.Met152Ile) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 34326862 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/NBN), 32885271 (2021), 30306255 (2018), 28528518 (2017), 26315354 (2015), 24894818 (2014), 23555315 (2013)), colorectal cancer (PMID: 27978560 (2016)), soft tissue sarcoma (PMID: 30541756 (2019)), and a myeloid malignancy (PMID: 31911633 (2020)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/NBN)). The frequency of this variant in the general population, 0.00034 (17/50746 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV000197783	SCV001481624	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2019-08-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000197783	SCV002045969	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000197783	SCV002526041	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-10-16	criteria provided, single submitter	clinical testing	The NBN c.456G>A (p.Met152Ile) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about the effect of this variant on protein function, and to our knowledge functional assays have not been performed. This variant has been reported in individuals with breast cancer, ovarian cancer, prostate cancer, colorectal cancer, and suspected Lynch syndrome (PMID: 25980754, 26315354, 27978560, 28135145, 28528518, 30306255, 32832836, 32885271), as well as in women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Nijmegen breakage syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sema4, Sema4	RCV000115795	SCV002536682	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000509203	SCV003813482	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467061	SCV004199487	uncertain significance	Aplastic anemia	2024-03-11	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000509203	SCV000607210	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
True Health Diagnostics	RCV000115795	SCV000886693	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000197783	SCV001461774	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356300	SCV001551428	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Met152Ile variant was identified in 4 of 10048 proband chromosomes (frequency: 0.0004) from individuals or families with colon, breast or ovarian cancer and was not identified in 6862 control chromosomes from healthy individuals (Cock-Rada 2018, Pearlman 2016, Ramus 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs201816949) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and five other submitters ). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 34 of 276952 chromosomes at a frequency of 0.0001 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 2 of 24016 chromosomes (freq: 0.00008), Other in 1 of 6454 chromosomes (freq: 0.0002), Latino in 2 of 34410 chromosomes (freq: 0.00006), European in 28 of 126568 chromosomes (freq: 0.0002), Finnish in 1 of 25714 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Met152 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV000509203	SCV001749946	not provided	not provided		no assertion provided	phenotyping only	Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Variant of Uncertain Significance by all laboratories and reported most recently on 3/23/2020 by Invitae and 3/4/2017 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.