Submissions for variant NM_002485.5(NBN):c.788T>C (p.Phe263Ser)

gnomAD frequency: 0.00059  dbSNP: rs147626427

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656926	SCV000149715	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	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 breast, ovarian, and other cancers (PMID: 23555315, 24549055, 25186627, 36346689); This variant is associated with the following publications: (PMID: 24549055, 25186627, 23555315, 34072463, 24894818, 36346689)
Ambry Genetics	RCV000115806	SCV000186194	benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199794	SCV000254780	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212737	SCV000595916	uncertain significance	not specified	2016-04-27	criteria provided, single submitter	clinical testing
Mendelics	RCV003492492	SCV000838308	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656926	SCV001134520	likely benign	not provided	2022-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212737	SCV001363750	likely benign	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: NBN c.788T>C (p.Phe263Ser) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of 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 0.00019 in 277060 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.788T>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Castera_2014, Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000199794	SCV002045949	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115806	SCV002536716	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004745190	SCV000806452	uncertain significance	NBN-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The NBN c.788T>C variant is predicted to result in the amino acid substitution p.Phe263Ser. This variant has been reported in multiple individuals in hereditary breast or ovarian cancer cohorts, as well as in a pan-cancer cohort; however, no additional functional studies or family segregation data are available to support its pathogenicity (Table S1, Castéra et al. 2014. PubMed ID: 24549055; Haiman et al. 2013. PubMed ID: 23555315; Tung et al. 2015. PubMed ID: 25186627; Belhadj et al. 2023. PubMed ID: 36346689). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD, a frequency higher than expected for a pathogenic allele in this gene. It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127880/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.