Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000043728 | SCV000071741 | benign | Hereditary breast ovarian cancer syndrome | 2024-01-16 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000759573 | SCV000108594 | likely benign | not provided | 2022-07-25 | criteria provided, single submitter | clinical testing | See Variant Classification Assertion Criteria. |
Ambry Genetics | RCV000131732 | SCV000186772 | likely benign | Hereditary cancer-predisposing syndrome | 2019-03-12 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Color Diagnostics, |
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, susceptibility to, 2 | 2017-04-05 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759573 | SCV000888974 | likely benign | not provided | 2023-01-17 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000212295 | SCV000918936 | likely benign | not specified | 2023-10-13 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.10222A>T (p.Lys3408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein by 10 amino acids and is not expected to undergo NMD. The variant allele was found at a frequency of 2.6e-05 in 152220 control chromosomes, and was also found in a woman >70 years of age who has never had cancer (FLOSSIES). 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. c.10222A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign Based on the evidence outlined above, the variant was classified as likely benign. |
Breast Cancer Information Core |
RCV000112851 | SCV000145768 | benign | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
Department of Pathology and Laboratory Medicine, |
RCV000112851 | SCV000592318 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 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. |