ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8997G>A (p.Leu2999=) (rs80359804)

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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) RCV000114028 SCV000579174 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 RCV000045683 SCV000073696 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000165813 SCV000216560 likely benign Hereditary cancer-predisposing syndrome 2014-09-03 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.
Color Health, Inc RCV000165813 SCV000689166 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Mendelics RCV000114028 SCV001139241 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001711162 SCV001945435 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27616075)
Breast Cancer Information Core (BIC) (BRCA2) RCV000114028 SCV000147508 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501626 SCV000592245 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Leu2999Leu variant was shown to have no effect on exon 23 splicing in a functional assay using hybrid minigene construction (Sanz 2010). In addition, a well-validated bioinformatics model applying information theory for splicing mutation analysis of BRCA1 and BRCA2 variants complemented this finding with the result of no concordant splicing effect (Mucaki 2010). The variant was also identified in dbSNP (ID: rs80359804) as “With Uncertain significance allele”, Clinvitae database (classifications: likely benign and uncertain significance), the ClinVar database (with conflicting interpretations of pathogenicity, classified as likely benign by Invitae and Ambry Genetics, and uncertain significance by BIC), the BIC database (1x with unknown clinical importance), UMD (3x with a ”unclassified variant” classification); in the NHLBI GO Exome Sequencing Project in 2 of 8590 European American alleles, (frequency: 0.00023), and the Exome Aggregation Consortium database (March 14, 2016) in 3 of 121072 chromosomes (freq. 0.00002), specifically in the Euorpean (Non-Finnish) population in 3 of 66564 chromosomes (freq.0.000045), but not in African, East Asian, Finnish, Latino, other and South Asian populations, increasing the likelihood this could be a low frequency benign variant. The p.Leu2999Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 likely benign.

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