Submissions for variant NM_002485.5(NBN):c.254A>G (p.Asn85Ser)

gnomAD frequency: 0.00002  dbSNP: rs587780095

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115791	SCV000149700	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Absent from cases but observed in controls in case-control studies assessing breast cancer, pancreatic cancer, or melanoma risk (Momozawa et al., 2018; Pritchard et al., 2018; Mizukami et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 29641532, 30287823, 32980694, 24894818, 33471991)
Ambry Genetics	RCV000214236	SCV000273223	likely benign	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000231493	SCV000287467	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000231493	SCV002045980	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115791	SCV002047130	uncertain significance	not provided	2022-12-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00075 (23/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In one study in the Japanese population, this variant was observed in 1/12490 male controls, but not among 7051 female and 53 male breast cancer patients or 11241 female controls (PMID: 30287823 (2018)). The variant was also observed in 1/1358 control individuals but not in 57 cases of melanoma with additional primary cancers (PMID: 29641532 (2018)). In a large scale breast cancer association study, this variant was reported in 2/53461 control individuals but not in 60466 women with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). Lastly, the variant was observed in 1/23705 control individuals but not in 1005 cases of pancreatic cancer (PMID: 32980694 (2020)). However since the age of onset and degree of elevated breast cancer risk by the NBN gene is not well defined (PMID: 2625988 (2015)), these reports do not unequivocally support a benign role of this variant. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000214236	SCV002536655	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Natera, Inc.	RCV000231493	SCV001461778	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing