ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9720T>C (p.Val3240=) (rs80359810)

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Total submissions: 14
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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) RCV000114157 SCV000578960 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; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV000167834 SCV000073904 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000045891 SCV000210691 benign not specified 2014-07-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162799 SCV000213280 likely benign Hereditary cancer-predisposing syndrome 2014-07-02 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590764 SCV000228420 uncertain significance not provided 2015-05-22 criteria provided, single submitter clinical testing
Counsyl RCV000114157 SCV000488763 likely benign Breast-ovarian cancer, familial 2 2016-06-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV000471010 SCV000541053 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045891 SCV000600876 likely benign not specified 2017-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162799 SCV000684088 likely benign Hereditary cancer-predisposing syndrome 2015-11-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590764 SCV000695265 likely benign not provided 2016-01-22 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 10/121302 (1/12195), predominantly found in the African cohort, 10/10370 (1/1037), which exceeds the maximum expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Therefore, suggesting that the variant of interest is a rare polymorphism specific to population(s) of African origin. The variant of interest has been reported in at least one affected individual via a publication, although with limited information (ie lack co-segregation data). However, an internal LCA sample reports the variant to co-occur with another probable pathogenic BRCA2 variant, c.2480dupA (p.N827fsX3 classified as likely pathogenic). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590764 SCV000889189 benign not provided 2017-08-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000045891 SCV001158020 benign not specified 2018-11-20 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000114157 SCV000147703 uncertain significance Breast-ovarian cancer, familial 2 2003-10-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353494 SCV000592304 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val3240Val 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, and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was not identified in the literature, but was identified in the BIC database (5X as a variant with unknown clinical importance), and in dbSNP (ID: rs80359810) “With untested allele”. The variant was identified in the NHLBI Exome Sequencing Project (Exome Variant Server) in 10 of 4406 African American chromosomes (frequency: 0.002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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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