Submissions for variant NM_002485.5(NBN):c.664T>C (p.Phe222Leu)

gnomAD frequency: 0.00005  dbSNP: rs541992192

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123219	SCV000166525	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 222 of the NBN protein (p.Phe222Leu). This variant is present in population databases (rs541992192, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, late-onset sporadic melanoma, leukemia, and/or uterine cancer (PMID: 17496786, 25503501, 34326862). ClinVar contains an entry for this variant (Variation ID: 136046). 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. 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	RCV000129030	SCV000172938	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-07	criteria provided, single submitter	clinical testing	The p.F222L variant (also known as c.664T>C), located in coding exon 6 of the NBN gene, results from a T to C substitution at nucleotide position 664. The phenylalanine at codon 222 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in an individual diagnosed with melanoma (Meyer P et al. Melanoma Res. 2007 Apr;17(2):109-16). This alteration has also been detected in multiple individuals diagnosed with breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000212734	SCV000211442	uncertain significance	not provided	2024-12-05	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; Observed in individuals with a personal or family history of melanoma, breast, leukemia, or other cancers, as well as in unaffected controls (PMID: 17496786, 25503501, 29522266, 34326862, 33471991); This variant is associated with the following publications: (PMID: 24396275, 17496786, 25503501, 33471991, 29522266, 34072463, 26580448, 37503171, 38446568, 34326862)
Counsyl	RCV000123219	SCV000794744	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212734	SCV000889555	uncertain significance	not provided	2024-09-19	criteria provided, single submitter	clinical testing	The NBN c.664T>C (p.Phe222Leu) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25503501 (2015), 29522266 (2018), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)), melanoma (PMID: 17496786 (2007)), leukemia (PMID: 26580448 (2015)), as well as reportedly healthy individuals (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000039 (5/128768 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Genome-Nilou Lab	RCV000123219	SCV002044819	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129030	SCV002536703	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002477323	SCV002790617	uncertain significance	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226205	SCV003922871	uncertain significance	not specified	2023-03-23	criteria provided, single submitter	clinical testing	Variant summary: NBN c.664T>C (p.Phe222Leu) results in a non-conservative amino acid change located in the second BRCT domain (IPR032429) 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 1.2e-05 in 250722 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.664T>C has been reported in the literature in an individual affected with melanoma with no family history of cancer, as a VUS in an individual affected with leukemia, and in an individual with a personal history of breast cancer and leukemia and an extensive family history of cancer, without strong evidence for causality (Meyer_2007, Maxwell_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467094	SCV004199572	uncertain significance	Aplastic anemia	2024-03-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000123219	SCV001457050	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-04-14	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212734	SCV002034889	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212734	SCV002035235	uncertain significance	not provided		no assertion criteria provided	clinical testing