ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10222A>T (p.Lys3408Ter) (rs80358402)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043728 SCV000071741 benign Hereditary breast and ovarian cancer syndrome 2020-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000759573 SCV000108594 likely benign not provided 2019-05-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10923033, 20104584)
Ambry Genetics RCV000131732 SCV000186772 likely benign Hereditary cancer-predisposing syndrome 2019-03-12 criteria provided, single submitter clinical testing Other data supporting benign classification
Color Health, Inc RCV000131732 SCV000683399 likely benign Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing
Counsyl RCV000112851 SCV000785078 likely benign Breast-ovarian cancer, familial 2 2017-04-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759573 SCV000888974 likely benign not provided 2019-08-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212295 SCV000918936 uncertain significance not specified 2018-01-12 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.10222A>T (p.Lys3408X) variant results in truncation of the last 10 amino acids in the last exon; therefore it is unexpected to cause nonsense-mediated decay. Truncations downstream of this position have not been classified as pathogenic by our laboratory and others in ClinVar. This variant was found in 3/296594 control chromosomes (gnomAD and FLOSSIES db) at a frequency of 0.0000101, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The BRCA2 c.9976A>T (p.Lys3326*) variant, located upstream of this variant and also in the last exon of the gene, is a known benign variant suggesting that the truncation of the last 93 amino acids of BRCA2 is unlikely to be pathogenic for breast and/or ovarian cancer. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories have recently classified this variant as likely benign (4), benign (1) or uncertain significance (1). Taken together this variant is classified as Variant of Unknown Significance-Possibly Benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112851 SCV000145768 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112851 SCV000592318 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Lys3408X variant was not identified in the literature but was identified in the BIC database (1X with no clinical importance), dbSNP (ID: rs80358402), and in the ClinVar database (classified as likely benign by GeneDx and Ambry Genetics; classified as benign by BIC; classification not provided by Invitae). The variant was listed in the Exome Aggregation Consortium (ExAC) database in 1 of 65858 chromosomes (frequency: 0.00002) from a population of European (Non-Finnish) individuals; however, this single observation and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant results in termination of translation at amino acid position 3408 and the loss of the terminal 9 amino acids of the expressed BRCA2 protein. Borg (2010) identified three variants in the BRCA2 gene near the 3’-end which were predicted to result in protein truncation (c.9976A>T (BIC: K3326X), c.10095delCins11 (BIC: 10323delCins11), c.10150C>T (BIC: R3384X), but were “ruled as exceptions that could not be classified because of their location near the 3’-end and possibly dispensable part of the gene”. The p.Lys3408X variant is located even farther downstream than these variants (i.e. closer to the 3’- end of the gene). Stop codon or nonsense mutations in the last exon of a gene may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. Segregation and/or functional studies are recommended to further elucidate the pathogenicity of this variant. 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 unknown significance.

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