ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.1262T>C (p.Leu421Ser) (rs104895032)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114875 SCV000149689 likely benign not provided 2021-05-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25980754, 26315354, 23555315, 20805886, 28135145, 28873162, 28726808, 30374176, 31278556)
Invitae RCV000123203 SCV000166508 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115780 SCV000183761 likely benign Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Insufficient evidence;No disease association in appropriately sized case-control study(ies);Other data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV000123203 SCV000475294 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics,Fulgent Genetics RCV000515275 SCV000611485 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000115780 SCV000680451 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212745 SCV000697942 likely benign not specified 2021-06-28 criteria provided, single submitter clinical testing Variant summary: NBN c.1262T>C (p.Leu421Ser) 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 0.00037 in 260122 control chromosomes in the gnomAD database, including 1 homozygote. The variant was also reported in 7 European American women older than age 70 years who have never had cancer. This data provide supporting evidence for a benign role. c.1262T>C has been reported in the literature in individuals affected with CVID, OvC, HBOC, Lynch syndrome and PDAC (e.g. Offer_2010, Ramus_2015, Tung_2015, Yurgelun_2015, 2017, Chaffee_2018, Dorling_2021) but it was also reported in multiple controls (Offer_2010, Ramus_2015, Dorling_2021). Additionally, evidence of non co-segregation with disease was provided through the study of a large family affected with different types of cancer including breast cancer (Tsai_2019), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and eight ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000123203 SCV000799755 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000114875 SCV000806410 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000757930 SCV000886451 likely benign Familial cancer of breast 2018-05-29 criteria provided, single submitter research The NBN variant designated as NM_002485.4: c.1262T>C (p.Leu421Ser) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yields a likelihood ratio of 1.88 to 1 that the allele is causing cancer in the family (Thompson et al, 2003, PMID:2900794, Damiola et al, 2014, PMID:24894818). However, this variant is found in approximately 1 out of 120 individuals of Ashkenazi Jewish ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic NBN variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 127009) and has been classified as benign by another clinical laboratory. Computer software programs also predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter NBN function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Health, Inc RCV000115780 SCV000910585 likely benign Hereditary cancer-predisposing syndrome 2015-12-11 criteria provided, single submitter clinical testing
Mendelics RCV000123203 SCV001137663 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-05-28 criteria provided, single submitter clinical testing
Harris Lab, University of Minnesota RCV000114875 SCV000148770 not provided not provided no assertion provided not provided
True Health Diagnostics RCV000115780 SCV000886692 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358304 SCV001554001 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Leu421Ser variant was identified in 5 of 11992 proband chromosomes (frequency: 0.0004) from individuals or families with antibody deficiency syndromes IgAD or CVID, ovarian cancer or Lynch syndrome and was present in 3 of 8746 control chromosomes (frequency: 0.0005) from healthy individuals (Offer 2010, Ramus 2015, Yurgelun 2015, Yurgelun 2017). The variant was also found in Genome-Wide testing of putative functional exonic variants with relative risk 1.224 and P=0.87 (Haiman 2013). The variant was identified in dbSNP (ID: rs104895032) as "With other allele", and in ClinVar (classified as benign by Invitae; as uncertain significance by eight submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 105 of 277090 chromosomes (1 homozygous) at a frequency of 0.0004 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 6 of 24016 chromosomes (freq: 0.0003), Other in 3 of 6458 chromosomes (freq: 0.0005), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 44 of 126620 chromosomes (freq: 0.0004), Ashkenazi Jewish in 43 of 10152 chromosomes (freq: 0.004), Finnish in 8 of 25790 chromosomes (freq: 0.0003), while the variant was not observed in the East Asian, and South Asian populations. The p.Leu421 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000114875 SCV001797367 likely benign not provided no assertion criteria provided clinical testing

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