ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9235G>A (p.Val3079Ile) (rs55933907)

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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) RCV000031803 SCV000244492 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 = 0.00002
Invitae RCV000167789 SCV000073766 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000120369 SCV000210681 likely benign not specified 2018-02-28 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 RCV000162558 SCV000212968 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.
Counsyl RCV000031803 SCV000220450 likely benign Breast-ovarian cancer, familial 2 2014-06-23 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120369 SCV000228108 likely benign not specified 2016-01-25 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031803 SCV000267829 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000167789 SCV000296862 likely benign Hereditary breast and ovarian cancer syndrome 2015-11-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768641 SCV000324843 likely benign Breast and/or ovarian cancer 2015-09-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283565 SCV000602840 likely benign none provided 2019-10-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162558 SCV000902658 benign Hereditary cancer-predisposing syndrome 2015-10-12 criteria provided, single submitter clinical testing
Mendelics RCV000031803 SCV001139250 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001114169 SCV001272014 uncertain significance Fanconi anemia, complementation group D1 2018-01-23 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000031803 SCV001272015 likely benign Breast-ovarian cancer, familial 2 2018-01-23 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Research and Development, ARUP Laboratories RCV001642507 SCV001852836 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031803 SCV000054411 likely benign Breast-ovarian cancer, familial 2 2008-09-23 no assertion criteria provided clinical testing
ITMI RCV000120369 SCV000084521 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031803 SCV000147574 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656625 SCV000778724 likely benign not provided 2017-05-19 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354579 SCV001549227 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val3079Ile variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was not identified in 1362 control chromosomes from healthy individuals (Bodian, 2014, Borg 2010). The variant was also identified in dbSNP (ID: rs55933907) as With other allele, ClinVar (classified as benign by ENIGMA, Ambry Genetics, Invitae; classified as likely benign by GeneDx, Counsyl, SCRP), Clinvitae (classified as benign by ClinVar, Invitae), LOVD 3.0 (5X predicted neutral), UMD-LSDB (11X likely neutral), BIC Database (22X with unknown significance), ARUP Laboratories ( not pathogenic or of no clinical significance ), databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 90 of 276464 chromosomes at a frequency of 0.000326 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Val3079 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the BRCA2, oligonucleotide/oligosaccharide-binding 3 Nucleic acid-binding, OB-fold Breast cancer type 2 susceptibility protein functional domains increasing the likelihood that it may have clinical significance. In addition, multifactorial probability based model for classification of BRCA1 and BRCA2 variants of uncertain significance classified the variant as neutral with posterior probability of being deleterious 2.00√ó10-5 (Lindor 2012). 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 likely benign.

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