ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4187A>G (p.Gln1396Arg) (rs55969723)

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Total submissions: 21
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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) RCV000031467 SCV000244447 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000895
Invitae RCV000044368 SCV000072381 benign Hereditary breast and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000120320 SCV000108614 likely benign not specified 2017-10-13 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 RCV000162521 SCV000212915 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768594 SCV000219336 likely benign Breast and/or ovarian cancer 2017-06-15 criteria provided, single submitter clinical testing
Counsyl RCV000031467 SCV000220847 likely benign Breast-ovarian cancer, familial 2 2014-10-29 criteria provided, single submitter literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000044368 SCV000257610 likely benign Hereditary breast and ovarian cancer syndrome 2015-06-08 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000044368 SCV000267844 likely benign Hereditary breast and ovarian cancer syndrome 2016-04-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044368 SCV000494367 benign Hereditary breast and ovarian cancer syndrome 2014-04-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120320 SCV000538474 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.6% (60/9946) African; ClinVar: 7B/LB, 1 VUS
Color Health, Inc RCV000162521 SCV000683603 likely benign Hereditary cancer-predisposing syndrome 2015-03-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031467 SCV000744452 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000031467 SCV001139084 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656602 SCV001148983 likely benign not provided 2018-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287206 SCV001473868 benign none provided 2019-09-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031467 SCV000054072 benign Breast-ovarian cancer, familial 2 2008-12-01 no assertion criteria provided clinical testing
ITMI RCV000120320 SCV000084472 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031467 SCV000146388 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000031467 SCV000207342 likely benign Breast-ovarian cancer, familial 2 2014-11-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353441 SCV000591894 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Gln1396Arg variant is found 5 times in UMD and 38 times in the BIC database. It was identified in the literature 3 of 4261 probands with unilateral and contalateral breast cancer patients, although an inadequate number of control chromosomes were tested to establish the variants frequency in the general population (Capanu 2011, Adem 2003, Borg 2009). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs55969723) with an average heterozygosity of 0.004+/-0.043 in the human population, increasing the likelihood that this is a low frequency benign variant. It was also found in the NHLBI Exome Sequencing Project (Exome Variant Server) with a frequency of 0.002 and was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) along with GeneDx and BIC with uncertain significance and ITMI and Invitae who did not provide an assessment. The p.Gln1396 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In the UMD database, this variant has been identified in one individual with a second pathogenic variant and a breast or ovarian cancer phenotype, thereby increasing the likelihood that this variant does not have clinical significance. In summary, 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 Benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656602 SCV000778672 likely benign not provided 2017-08-02 no assertion criteria provided clinical testing

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