ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.340G>T (p.Val114Phe)

dbSNP: rs771034958
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206877 SCV000259635 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 114 of the NBN protein (p.Val114Phe). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and family history of breast cancer, uterine cancer and ovarian cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 219644). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics RCV000220601 SCV000273508 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-09 criteria provided, single submitter clinical testing The p.V114F variant (also known as c.340G>T), located in coding exon 4 of the NBN gene, results from a G to T substitution at nucleotide position 340. The valine at codon 114 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in 1/45 Lebanese patients with reported family history of breast cancer who were tested with whole-exome sequencing (Jalkh N et al. BMC Med Genomics, 2017 02;10:8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000767209 SCV000566663 uncertain significance not provided 2022-09-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast cancer, but also in unaffected controls (Jalkh et al., 2017; Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 28202063, 24894818, 30287823)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486552 SCV000601689 uncertain significance not specified 2017-07-21 criteria provided, single submitter clinical testing
Counsyl RCV000206877 SCV000794974 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-10-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764790 SCV000895934 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000206877 SCV002045229 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV003474978 SCV004199519 likely pathogenic Aplastic anemia 2023-10-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV000206877 SCV002078668 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-28 no assertion criteria provided clinical testing

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