ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131226 SCV000186180 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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 likely benign Microcephaly, normal intelligence and immunodeficiency 2017-12-13 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 RCV000131226 SCV000685768 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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

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