ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7436-4A>G (rs81002904)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084165 SCV000073228 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000168599 SCV000210421 uncertain significance not specified 2017-05-16 criteria provided, single submitter clinical testing The BRCA2 c.7436-4A>G variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 c.7436-4A>G was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The adenine (A) nucleotide that is altered is not conserved. In silico models are uninformative with respect to splicing, and in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 c.7436-4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000164776 SCV000215452 benign Hereditary cancer-predisposing syndrome 2015-04-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768634 SCV000219393 uncertain significance Breast and/or ovarian cancer 2017-07-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000168599 SCV000600750 uncertain significance not specified 2017-06-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168599 SCV000695067 likely benign not specified 2019-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7436-4A>G 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. 5/5 computational tools predict no significant impact on normal splicing. In addition, at least two publications reported experimental evidence demonstrating that the variant does not impact normal splicing, in either patient derived mRNA (Wangensteen_2019) or in a minigene assay (Fraile-Bethencourt_2019). The variant allele was found at a frequency of 1.6e-05 in 251022 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7436-4A>G has been reported in the literature in at least one individual screened for Hereditary Breast and Ovarian Cancer (Wangensteen_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: three cited the variant as uncertain significance and three as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000164776 SCV000910822 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031679 SCV000054286 uncertain significance Breast-ovarian cancer, familial 2 2012-03-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031679 SCV000147086 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353462 SCV000592110 uncertain significance not provided no assertion criteria provided clinical testing The c.7436-4A>G variant has not been previously identified in the literature but has been identified in one individual with breast cancer in our laboratory. This individual met the ministry of health of ontario categories 7 (two cases of breast cancer, both <50 years, in first or second-degree relatives) and 10 (three or more cases of breast or ovarian cancer at any age). This 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. Computational or in-silico analyses do not demonstrate altered splicing in 4 of the splice prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, HumanSpliceFinder), increasing the possibility that this may be a benign variant. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance.

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