ClinVar Miner

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

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Total submissions: 11
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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 RCV001082574 SCV000073389 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 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 2018-08-15 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000163206 SCV000910870 likely benign Hereditary cancer-predisposing syndrome 2015-12-04 criteria provided, single submitter clinical testing
Mendelics RCV000494843 SCV001139201 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353768 SCV000592167 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Ile2664Ile has been identified in UMD (6X) and the BIC (1X) databases. It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359800) with a “global minor allele frequency of less than 0.001 (1000 genomes). This variant is not expected to have clinical significance because it does not alter an amino acid residue, however it has been suggested to induce incomplete skipping of exon 18 of BRCA2 detected by minigene and in vivo assays (Thery 2011); yet in–silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance (VUS).
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
King Laboratory,University of Washington RCV001171450 SCV001251361 pathogenic Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000589588 SCV001955500 likely benign not provided no assertion criteria provided clinical testing

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