ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.476-3C>T (rs371431745)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132383 SCV000187474 likely benign Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
GeneDx RCV000438966 SCV000518263 likely benign not specified 2017-11-20 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.
Invitae RCV000559561 SCV000635404 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37925). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000132383 SCV000905899 likely benign Hereditary cancer-predisposing syndrome 2018-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000438966 SCV001467840 uncertain significance not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.476-3C>T alters a 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. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.476-3C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3, VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000031506 SCV000054111 uncertain significance Breast-ovarian cancer, familial 2 2011-12-02 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356001 SCV001551048 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 c.476-3C>T variant was not identified in the literature and the UMD-LSDB database. The variant was identified in dbSNP (rs371431745) as “with pathogenic, uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 2 others and "likely benign" by Ambry Genetics) and LOVD-3.0 (observed 3x). The variant was identified in control databases in 1 of 30,714 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 14,884 chromosomes (freq: 0.00007). The variant was not observed in the African, Other, Latino. Ashkenazi Jewish. East Asian, Finnish and South Asian populations. The c.476-3C>T 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, a variant at the same splice site (c.476-3C>A) was demonstrated to cause aberrant splicing and was classified as pathogenic (Fraile-Bathencourt 2019). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This is classified as a variant of uncertain significance.

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