ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.223G>C (p.Ala75Pro) (rs28897701)

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Total submissions: 20
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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) RCV000077274 SCV000244429 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 = 0.00000000928
Invitae RCV000043960 SCV000071973 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000120382 SCV000167398 benign not specified 2013-10-14 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.
CSER _CC_NCGL, University of Washington RCV000148426 SCV000190125 likely benign Breast neoplasm 2014-06-01 criteria provided, single submitter research
Michigan Medical Genetics Laboratories,University of Michigan RCV000077274 SCV000195946 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162508 SCV000212899 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 RCV000768584 SCV000219278 likely benign Breast and/or ovarian cancer 2016-12-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120382 SCV000538480 uncertain significance 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: Multiple publications classify as VUS/notpathogenic; ExAC: 17/66638 European chromosomes
Baylor Genetics RCV000457418 SCV000541074 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283410 SCV000602764 likely benign none provided 2020-03-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513224 SCV000608676 likely benign not provided 2017-06-01 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162508 SCV000679706 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162508 SCV000683473 likely benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000513224 SCV000805670 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Mendelics RCV000043960 SCV000838723 likely benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000077274 SCV001138947 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120382 SCV000084534 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077274 SCV000109071 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077274 SCV000146403 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 RCV000120382 SCV000591664 benign not specified no assertion criteria provided clinical testing The BRCA2 p.Ala75Pro variant was identified in 6 of 9140 proband chromosomes (frequency: 0.001) from individuals with breast, ovarian, or prostate cancer (Borg 2010, de SanJose 2003, Kote-Jarai 2011, Soegaard 2008); however, control chromosomes were not analyzed from these studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs28897701) “With non-pathogenic allele”, HGMD, UMD (91X as a neutral variant), and the BIC database (51X with unknown clinical importance). The variant was listed in the NHLBI Exome Sequencing Project in 4 of 8600 European American alleles (frequency: 0.0005), increasing the likelihood that it may be a low frequency benign variant in certain populations. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. One functional study found no effect of the variant on mRNA transcript levels as compared to wildtype, and two multifactorial based models predict the variant to be non-pathogenic or of no clinical significance (Muller 2011, Capanu 2011, Lindor 2012). In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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