ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.456G>A (p.Met152Ile) (rs201816949)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000509203 SCV000149704 uncertain significance not provided 2021-04-19 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history including breast, ovarian, colorectal, and other cancers (Haiman 2013, Yurgelun 2015, Ramus 2015, Pearlman 2017, Yurgelun 2017, Cock-Rada 2018); 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: 25980754, 26787654, 26315354, 23555315, 27978560, 28528518, 28135145, 30306255)
Ambry Genetics RCV000115795 SCV000186697 likely benign Hereditary cancer-predisposing syndrome 2020-06-05 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000197783 SCV000254776 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 152 of the NBN protein (p.Met152Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs201816949, ExAC 0.02%). This variant has been reported in individuals with Lynch syndrome-associated cancer and/or colon polyps (PMID: 25980754, 28135145), and an individual with serous ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 127872). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000509203 SCV000344520 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115795 SCV000537561 likely benign Hereditary cancer-predisposing syndrome 2020-07-20 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 uncertain significance not specified 2021-04-16 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, one database reported this variant was found in seven women older than age 70 years who have never had cancer. 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 reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a BRCA2 pathogenic variant has been internally reported (c.5864C>A, p.Ser1955X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=10, likely benign n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Clinical Services Laboratory,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 2020-08-13 criteria provided, single submitter clinical testing
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].
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.

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