Submissions for variant NM_002485.5(NBN):c.1809C>A (p.Phe603Leu)

gnomAD frequency: 0.00014  dbSNP: rs192236678

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164543	SCV000215199	likely benign	Hereditary cancer-predisposing syndrome	2021-08-02	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	RCV001081367	SCV000219123	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000589243	SCV000513863	likely benign	not provided	2021-01-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24349281, 25712764, 26315354, 23555315, 30942098, 32668560)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000424535	SCV000601678	benign	not specified	2019-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589243	SCV000697955	benign	not provided	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The NBN c.1809C>A (p.Phe603Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 40/128334 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.004161 (36/8652). This frequency is about 33 times the estimated maximal expected allele frequency of a pathogenic NBN variant (0.000125), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. his variant was reported in two studies in non-BRCA1/2 Korean patients with high-risk breast cancer and European populations with high risk of ovarian cancer, but was also observed in controls (Kim_FC_2015, Ramus_NBN1_JNCI_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Eurofins Ntd Llc (ga)	RCV000424535	SCV000707503	likely benign	not specified	2017-04-17	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030565	SCV001193655	likely benign	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001081367	SCV001324785	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001081367	SCV002045903	benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164543	SCV002536620	benign	Hereditary cancer-predisposing syndrome	2020-12-15	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357000	SCV001552319	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Phe603Leu variant was identified in 7 of 7106 proband chromosomes (frequency: 0.001) from individuals or families with hepatocellular carcinoma, breast or ovarian cancer (Kim 2015, Ramus 2015, Wang 2013). The variant was also identified in dbSNP (ID: rs192236678) as "With Likely benign allele ", ClinVar (classified as benign by Invitae, Integrated Genetics/Laboratory Corporation of America; as likely bening by Ambry Genetics, GeneDx, and two clinical laboratories), and in LOVD 3.0 (1x) databases. The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 102 of 276468 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 98 of 18856 chromosomes (freq: 0.005), and South Asian in 4 of 30768 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, and Finnish populations. The p.Phe603 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.