ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7992T>A (p.Ile2664=) (rs80359800)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000494843 SCV000579007 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Invitae RCV000589588 SCV000073389 likely benign not provided 2019-02-20 criteria provided, single submitter clinical testing
GeneDx RCV000589588 SCV000210455 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7992T>A at the DNA level. Using alternate nomenclature, this variant would be defined as BRCA2 8220T>A. Although the variant is silent at the coding level, preserving an Isoleucine at codon 2664, it has been demonstrated to cause abnormal splicing. However, the splicing error has been characterized as having a partial, or leaky, effect, with some full length transcript also being produced (Th?ry 2011, Houdayer 2012). BRCA2 c.7992T>A has been reported in a patient with bilateral breast cancer and a family history of early onset breast cancer (Th?ry 2011). BRCA2 c.7992T>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a thymine (T) at base 7992, is conserved among mammals. Based on currently available information, it is unclear whether BRCA2 c.7992T>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000163206 SCV000213729 likely benign Hereditary cancer-predisposing syndrome 2014-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045376 SCV000592167 uncertain significance not specified 2012-05-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045376 SCV000695118 uncertain significance not specified 2019-09-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7992T>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts that this variant is Benign. However, splicing functional assays demonstrated the variant increases skipping of exon 18 (Thery_2011, Houdayer_2012, Fraile-Bethencourt_2017), however It is complex to interpret the role of variants with partial splicing anomalies in HBOC under the clinical perspective. The variant allele was found at a frequency of 3.2e-05 in 250460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7992T>A, has been reported in the literature in one individual affected with breast cancer (Thery_BRCA2_EJHG_2011). The data does not allow any conclusion about variant significance. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2, likely benign, n=2) and one expert panel (ENIGMA) classified this variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign
Color RCV000163206 SCV000910870 likely benign Hereditary cancer-predisposing syndrome 2015-12-04 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735606 SCV000863744 uncertain significance Breast and/or ovarian cancer 2015-08-07 no assertion criteria provided clinical testing

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