ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2127G>C (p.Leu709=) (rs554040246)

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Total submissions: 10
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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) RCV000495711 SCV000578025 benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0013 (East Asian), derived from ExAC (2014-12-17).
Ambry Genetics RCV000164090 SCV000214701 likely benign Hereditary cancer-predisposing syndrome 2014-09-11 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.
Invitae RCV001082804 SCV000252605 benign Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240769 SCV000265951 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Color Health, Inc RCV000164090 SCV000683468 likely benign Hereditary cancer-predisposing syndrome 2016-05-29 criteria provided, single submitter clinical testing
Counsyl RCV000495711 SCV000786148 benign Breast-ovarian cancer, familial 2 2018-03-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195970 SCV001133700 benign not provided 2018-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000495711 SCV001139021 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501646 SCV001362880 benign not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2127G>C alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 245968 control chromosomes, predominantly at a frequency of 0.00099 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant has been described in several sequencing studies in patients of Eastern Asian origin consistent with the occurrences seen in the gnomAD database. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four of whom classified the variant as benign (n=4)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353815 SCV000591790 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Leu709Leu 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.The p.Leu709Leu variant was identified in the literature in 3 of 3330 proband chromosomes (frequency: 0.001) from individuals with breast cancer and was not identified in 972 control chromosomes from these studies (Kim 2006, Suter 2004). The variant was not identified in any databases searched, including: dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC, and UMD. 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 predicted benign.

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