ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8905G>A (p.Val2969Met) (rs59004709)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077456 SCV000244488 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 = 0.000011
Invitae RCV001080800 SCV000073664 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000077456 SCV000154091 likely benign Breast-ovarian cancer, familial 2 2014-03-20 criteria provided, single submitter literature only
GeneDx RCV001719798 SCV000210675 likely benign not provided 2020-10-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21232165, 18559594, 21965345, 18375895, 20104584, 25948282, 26780556, 24323938, 28324225, 28678401, 17924331, 21990134, 29884841)
Ambry Genetics RCV000163015 SCV000213503 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755866 SCV000883493 likely benign none provided 2020-06-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163015 SCV000910612 likely benign Hereditary cancer-predisposing syndrome 2015-07-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000077456 SCV001270520 uncertain significance Breast-ovarian cancer, familial 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001112821 SCV001270521 uncertain significance Fanconi anemia, complementation group D1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Research and Development, ARUP Laboratories RCV001646856 SCV001852817 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) RCV000077456 SCV000109254 uncertain significance Breast-ovarian cancer, familial 2 2006-11-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077456 SCV000147483 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 RCV001353409 SCV000592236 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val2969Met variant was identified in 6 of 9554 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 80 control chromosomes from healthy individuals (Akbari 2011, Borg 2010, Soegaard 2008, Stegel 2011, Kluska 2015). The variant was also identified by our laboratory in 1 individual with hereditary breast and ovarian cancer. The variant was also identified in dbSNP (ID: rs59004709) as “other”, Clinvitae database (as benign), Fanconi Anemia Mutation Database -LOVD (3x, as predicted neutral 2x and predicted deleterious 1x), LOVD-IARC database (as not pathogenic), ARUP Laboratories BRCA Mutations Database (as not pathogenic), the ClinVar database (as benign, reviewed by an expert panel), GeneInsight COGR database (as “benign”, “likely benign”, and “unknown significance”, by clinical laboratories), the BIC database (24x with unknown clinical importance), and UMD (23x with a “likely neutral” classification). This variant was identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), NHLBI GO Exome Sequencing Project in 2 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 49 of 120422 chromosomes (freq. 0.0004) in the following populations: European (Non-Finnish) in 41 of 66196 chromosomes (freq. 0.0006), European (Finnish) in 4 of 6614 chromosomes (freq. 0.0006), and African in 4 of 10180 chromosomes (freq. 0.0004), but was not seen in East Asian, Latino, South Asian and other populations, increasing the likelihood this could be a low frequency benign variant. There is conflicting information in the literature. Two in-silico functional studies suggest this variant is predicted neutral (Easton 2007, Lindor 2012), while two others suggest the variant is likely deleterious (Karchin 2008, Kluska 2015). The p.Val2969 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000168609 SCV001905817 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000168609 SCV001952716 benign not specified no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.