ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.794-11T>C (rs81002822)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045349 SCV000073362 benign Hereditary breast and ovarian cancer syndrome 2020-10-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580896 SCV000683918 likely benign Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000504042 SCV000730712 benign not specified 2015-06-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000112830 SCV000743250 likely benign Breast-ovarian cancer, familial 2 2015-06-15 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000112830 SCV000744393 likely benign Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Counsyl RCV000112830 SCV000785118 likely benign Breast-ovarian cancer, familial 2 2017-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000504042 SCV000917051 benign not specified 2021-08-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.794-11T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. This is supported by functional studies that have reported no impact on splicing (example, Houdayer_2012). The variant allele was found at a frequency of 2.9e-05 in 242116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.794-11T>C has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with breast and/or colorectal cancer (example, Brandao_2011, Djursby_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the UMD database and observed at our laboratory (UMD - BRCA1 c.2649insGGCA, p.Thr884AlafsX20; BRCA1 c.5106delA, p.Lys1702AsnfsX4; Our laboratory - BRCA1 c.5266dupC, p.Gln1756fsX74), providing supporting evidence for a benign role. 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 (n=2)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112830 SCV000145741 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353607 SCV000591714 likely benign not provided no assertion criteria provided clinical testing The BRCA2, EXON10, c.794-11T>C, variant was identified in at least one breast and/or ovarian cancer family from a cohort of 1800 unrelated probands (Brandao 2011). The variant was also identified in the UMD (1X as an unclassified variant) and in the BIC database (3X with unknown clinical importance). The c.794-11T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. One functional study using RT-PCR analysis demonstrated no effect of the variant on splicing (Brandao 2011). In addition, in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) does not predict a difference in splicing all four programs. Furthermore, this variant was identified by our laboratory in an individual with a co-occurring pathogenic mutation in BRCA1, increasing the likelihood that the c.794-11T>C variant does not have clinical importance. 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 predicted benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV001353607 SCV001906303 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001353607 SCV001954252 likely benign not provided no assertion criteria provided clinical testing

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