ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.278C>T (p.Ser93Leu) (rs12721593)

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Total submissions: 11
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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 Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000193311 SCV000211471 uncertain significance not specified 2017-09-15 criteria provided, single submitter clinical testing This variant is denoted NBN c.278C>T at the cDNA level, p.Ser93Leu (S93L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been identified in at least one individual with a history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). NBN Ser93Leu was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Ser93Leu occurs at a position that is not conserved and is located in the BRCT2 domain (Damiola 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether NBN Ser93Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168344 SCV000219033 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-07 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000193311 SCV000248136 uncertain significance not specified 2015-01-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131226 SCV000685768 likely benign Hereditary cancer-predisposing syndrome 2020-01-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586867 SCV000697965 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The NBN c.278C>T (p.Ser93Leu) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant, however they are not definitive and no published functional studies are currently available. This variant was found in 88/121286 control chromosomes (including one homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.0044237 (73/16502). This frequency is about 1.8 times the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025), suggesting this is may be a rare benign polymorphism found primarily in the populations of South Asian origin. This variant has been reported in one BCP-ALL (B cell precursor acute lymphoblastic leukemia) patient in literature (Varon_2001) without strong evidence for pathogenicity. The patient's germline was not available so as to confirm whether it was a germline or somatic. In another study that screened constitutional (remission) DNA samples from 231 United Kingdom children with primary leukemia and 90 children with primary lymphoma, this variant was not found; therefore the authors say that it failed to show a significant contribution to susceptibility to these diseases (Taylor_2003). It was also absent in a cohort of 3236 invasive epithelial ovarian cancer patients while was found once in 3431 control patients of European origin (Ramus_2014). In ClinVar, it is classified as likely benign by a lab while other two classify it as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Counsyl RCV000168344 SCV000799694 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-04-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131226 SCV000822085 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina 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.
Nilou-Genome Lab RCV000168344 SCV001652739 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System 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.

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