ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1011C>T (p.Asn337=) (rs41293473)

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Total submissions: 12
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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) RCV000112874 SCV000578713 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 RCV001080288 SCV000071729 benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163333 SCV000213867 likely benign Hereditary cancer-predisposing syndrome 2014-09-22 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 RCV000724514 SCV000224770 uncertain significance not provided 2015-01-08 criteria provided, single submitter clinical testing
Counsyl RCV000112874 SCV000489615 likely benign Breast-ovarian cancer, familial 2 2016-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000173639 SCV000512336 benign not specified 2015-04-15 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.
Baylor Genetics RCV000467442 SCV000541067 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163333 SCV000683394 likely benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000724514 SCV000888971 likely benign not provided 2018-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173639 SCV000918934 likely benign not specified 2020-07-09 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112874 SCV000145804 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353646 SCV000591725 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Asn372Asn variant was identified in 1 of 762 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs41293473) “With uncertain significance allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), Clinvitae database, COSMIC 1X, the ClinVar database 5X with conflicting interpretations (2X as likely benign and 3X with uncertain significance), the BIC database (1X with unknown clinical importance), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 10050 chromosomes (frequency: 0.0002) from a population of African individuals and in 2 of 66314 chromosomes (frequency: 3.02x10-3) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (p.Phe1559LeufsX9), increasing the likelihood that the p.Asn337Asn variant does not have clinical significance. The p.Asn337Asn 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 summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as benign.

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