Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131226 | SCV000186180 | likely benign | Hereditary cancer-predisposing syndrome | 2019-07-01 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Gene |
RCV000586867 | SCV000211471 | likely benign | not provided | 2020-12-23 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 25980754, 11325820, 14559852, 28135145, 25176580, 19452044, 15279809, 26315354, 31278556, 31159747) |
Invitae | RCV000168344 | SCV000219033 | benign | Microcephaly, normal intelligence and immunodeficiency | 2024-01-31 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000193311 | SCV000248136 | uncertain significance | not specified | 2015-01-13 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000193311 | SCV000697965 | likely benign | not specified | 2021-12-17 | criteria provided, single submitter | clinical testing | Variant summary: NBN c.278C>T (p.Ser93Leu) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251486 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.278C>T has been reported in the literature in individuals affected with cancer (example: Varon_2001, Taylor_2003, Ramus_2015, Yurgelun_2017, Tsaousis_2019, Dorling_2021). These data do not allow any conclusion about variant significance with Nijmegen Breakage Syndrome or increase risk in cancer. Co-occurrence with other pathogenic variants has been reported (BRCA c.7251_7252delCA, p.H2417fs*3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. |
Counsyl | RCV000168344 | SCV000799694 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2018-04-29 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000131226 | SCV000822085 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV000168344 | SCV001324901 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2018-01-12 | 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. |
Genome- |
RCV000168344 | SCV001652739 | uncertain significance | Microcephaly, normal intelligence and immunodeficiency | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000131226 | SCV002536658 | likely benign | Hereditary cancer-predisposing syndrome | 2021-02-01 | criteria provided, single submitter | curation | |
ARUP Laboratories, |
RCV000586867 | SCV003800289 | likely benign | not provided | 2022-09-12 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354986 | SCV001549731 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The NBN p.Ser93Leu variant was identified in 1 of 94 proband chromosomes (frequency: 0.01) from German individuals or families with acute lymphocytic leukemia (ALL) and was not identified in 110 control chromosomes from healthy individuals (Varon 2001). The variant was also identified in dbSNP (ID: rs12721593 “With Uncertain significance allele”), ClinVar (1x as likely benign by Invitae and 3x as uncertain significance by Ambry Genetics, GeneDx, and Genetic Services Laboratory at University of Chicago), LOVD 3.0 (1x), and the Zhejiang University Database (3x). The variant was also identified in control databases in 148 of 246182 chromosomes (2 homozygous) at a frequency of 0.0006 (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 15292 chromosomes (frequency: 0.00007), Latino in 3 of 33576 chromosomes (frequency 0.00009), European Non-Finnish in 11 of 111668 chromosomes (frequency: 0.0001) and South Asian in 133 of 30778 chromosomes (2 homozygous, frequency: 0.004). The variant was not identified in Cosmic. The p.Ser93Leu variant occurs in the known FHA (forkhead associated) domain of nibrin that is probably involved in protein-protein interactions (Di Masi 2008, Digweed 2004). The p.Ser93 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Leu variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance. |