Submissions for variant NM_002485.5(NBN):c.448C>T (p.Leu150Phe)

gnomAD frequency: 0.00001  dbSNP: rs773119929

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001177301	SCV002635366	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	The p.L150F variant (also known as c.448C>T), located in coding exon 4 of the NBN gene, results from a C to T substitution at nucleotide position 448. The leucine at codon 150 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in one individual from a Finnish breast/ovarian cohort (Heikkinen K et al. J. Med. Genet., 2003 Dec;40:e131). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003156319	SCV003845714	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as NBS1 c.448; p.(L150F); Published functional studies demonstrate no damaging effect on protein stability (Williams et al., 2009); Observed in individuals with breast cancer (Heikkinen et al., 2003; Heikkinen et al., 2006); This variant is associated with the following publications: (PMID: 32025336, 14684699, 24894818, 32668560, 26075229, 20439160, 19804756, 24349281, 19804755, 16474176)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331062	SCV004037767	uncertain significance	not specified	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: NBN c.448C>T (p.Leu150Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.448C>T has been reported in the literature in individuals affected with Breast Cancer (Heikkinen_2003, Heikkinen_2006) and Acute Myeloid Leukemia (Shi_2011). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however structural models suggest the variant may impact the BRCT binding site (Wiliams_2009). The following publications have been ascertained in the context of this evaluation (PMID: 16474176, 14684699, 20232390, 19804755). Three ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV003507357	SCV004295243	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2022-12-10	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NBN function (PMID: 16474176, 19804755). ClinVar contains an entry for this variant (Variation ID: 919268). This missense change has been observed in individual(s) with breast cancer (PMID: 14684699, 16474176). This variant is present in population databases (rs773119929, gnomAD 0.03%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 150 of the NBN protein (p.Leu150Phe).