Submissions for variant NM_002485.5(NBN):c.1036G>A (p.Val346Met)

gnomAD frequency: 0.00011  dbSNP: rs200297914

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589164	SCV000149685	likely benign	not provided	2020-11-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23525077, 26976419, 27443514, 23555315)
Ambry Genetics	RCV000115776	SCV000186073	likely benign	Hereditary cancer-predisposing syndrome	2020-09-28	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.
Invitae	RCV001082179	SCV000261858	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589164	SCV000341709	uncertain significance	not provided	2016-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212741	SCV000697932	likely benign	not specified	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1036G>A (p.Val346Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251374 control chromosomes, predominantly at a frequency of 0.0033 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1036G>A has been reported in the literature in individuals affected with breast cancer, endometrial cancer and in unaffected controls (example, Haiman_2013, Tung_2016, Ring_2016, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome or with any of the NBN associated tumors. At-least two co-occurrences with other pathogenic variants have been observed at our laboratory (APC c.1206_1207delTG, p.Glu403AsnfsX15; BRCA2 c.6405_6409delCTTAA, p.Asn2135LysfsX3), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23555315, 26976419, 27443514, 30287823). Fourteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=9) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589164	SCV001134492	likely benign	not provided	2022-12-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082179	SCV001321724	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ACT Genomics,	RCV001255161	SCV001366120	likely benign	Malignant tumor of prostate	2020-06-22	criteria provided, single submitter	clinical testing	The allele frequency of this variant c.1036G>A (p.Val346Met) is 0.003 in East Asian of gnomAD Exomes and 0.002 in East Asian in 1000 Genomes. There is a small physicochemical difference between valine and methionine, which is not likely to impact secondary protein structure as these residues share similar properties. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign.
Baylor Genetics	RCV001293998	SCV001482744	uncertain significance	Aplastic anemia	2020-11-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001082179	SCV002045941	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212741	SCV002068221	uncertain significance	not specified	2018-04-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115776	SCV002536566	likely benign	Hereditary cancer-predisposing syndrome	2020-11-05	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000589164	SCV003813481	uncertain significance	not provided	2022-01-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945047	SCV004758494	likely benign	NBN-related disorder	2023-02-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001082179	SCV001457044	likely benign	Microcephaly, normal intelligence and immunodeficiency	2020-01-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355371	SCV001550243	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Val346Met variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs200297914) as “With Uncertain significance allele”, in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Invitae and uncertain significance by GeneDx, Ambry Genetics, EGL Genetic Diagnostics and Laboratory Corporation of America), Clinvitae (4x), Cosmic (1x in an adenocarcinoma of the oesophagus), and not identified in LOVD 3.0 and Zhejiang University Database. The variant was identified in control databases in 77 of 277100 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 3 of 34386 chromosomes (freq: 0.00009), European Non-Finnish in 2 of 126628 chromosomes (freq: 0.00002), East Asian in 62 of 18866 chromosomes (freq: 0.003), and South Asian in 10 of 30782 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish and Finnish populations. The p.Val346 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of the variant Met to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115776	SCV001977055	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing