ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1964C>G (p.Pro655Arg) (rs28897712)

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Total submissions: 22
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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) RCV000113003 SCV000244428 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 = 0.0000686
Invitae RCV000043931 SCV000071944 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000113003 SCV000154034 likely benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000168555 SCV000167339 benign not specified 2013-10-03 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 RCV000162572 SCV000212988 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 RCV000735527 SCV000219313 likely benign Breast and/or ovarian cancer 2016-11-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000168555 SCV000225171 likely benign not specified 2014-11-07 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000043931 SCV000296851 likely benign Hereditary breast and ovarian cancer syndrome 2015-09-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113003 SCV000383646 likely benign Breast-ovarian cancer, familial 2 2019-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV000168555 SCV000593707 benign not specified 2016-12-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168555 SCV000602834 benign not specified 2018-07-20 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162572 SCV000679710 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162572 SCV000683465 benign Hereditary cancer-predisposing syndrome 2015-04-15 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000113003 SCV000744423 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000168555 SCV000805661 benign not specified 2016-07-11 criteria provided, single submitter clinical testing
Mendelics RCV000113003 SCV001139020 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034434 SCV000043201 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113003 SCV000145988 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 RCV000168555 SCV000591785 benign not specified no assertion criteria provided clinical testing The p.Pro655Arg variant has been reported in the literature in 2 of 600 proband chromosomes of individuals with hereditary breast cancer and ovarian cancer, although no control chromosomes were tested to establish the frequency in the general population (Goldgar 2004, Frank 2002, Biswas 2012, Walsh 2006, Caux-Moncoutier 2009). Frank et al (2008) described the prevalence of this variant at >5% of the Ashkenazi Jewish population, supporting the likelihood that this variant has “little clinical consequence”. The p.Pro655 residue is not highly conserved in mammals; however, computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant is listed in the dbSNP database (ID#: rs28897712) with a minor allele frequency of <0.003. Functional studies including protein structure prediction, detection of full-length protein and sensitivity to DNA damaging reagents, predict this variant to be "non-pathogenic" (Biswas 2012). In the UMD database, this variant is considered to have “neutral” biological significance. The UMD database has also reported this variant in one individual (out of 8) with breast or ovarian cancer, where a second pathogenic BRCA2 mutation was also detected, and in another individual where a pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. This variant has been reported 142 times in the BIC database. The exome variant server has reported this variant in 10/13006 normal chromosomes. In summary, based on the above information, this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000034434 SCV000778651 likely benign not provided 2016-11-29 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162572 SCV000787922 benign Hereditary cancer-predisposing syndrome 2018-09-06 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735527 SCV000863665 benign Breast and/or ovarian cancer 2012-08-30 no assertion criteria provided clinical testing

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