ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1809C>A (p.Phe603Leu) (rs192236678)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164543 SCV000215199 likely benign Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV001081367 SCV000219123 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-07 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 RCV000589243 SCV000601678 benign not provided 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000424535 SCV000707503 likely benign not specified 2017-04-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164543 SCV000902625 benign Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030565 SCV001193655 likely benign Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,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.
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.

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