ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8215G>A (p.Val2739Ile) (rs80359069)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080912 SCV000073466 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129733 SCV000184538 likely benign Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000045453 SCV000278879 likely benign not provided 2021-09-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24094589, 26580448, 26689913, 25348012, 21702907, 19043619, 21218378, 25682074, 25556971)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000214196 SCV000494391 benign not specified 2021-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8215G>A (p.Val2739Ile) results in a conservative amino acid change located in the OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249656 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8215G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for pathogenicity (Carney_2010, Trujillano_2015, Wong-Brown_2015, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database and observed at our laboratory (BRCA2 c.6486_6489delACAA , p.Lys2162fsX5 at our laboratory; BRCA1 c.81-2delA in BIC database), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair activity and in a mouse embryonic stem cell-based cell survival plus drug sensitivity assay (Karchin_2008, Biswas_2020). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=6; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045453 SCV000600791 likely benign not provided 2020-02-18 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077431 SCV000744538 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Counsyl RCV000077431 SCV000785552 uncertain significance Breast-ovarian cancer, familial 2 2017-09-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129733 SCV000902886 likely benign Hereditary cancer-predisposing syndrome 2015-07-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001110061 SCV001267449 uncertain significance Fanconi anemia, complementation group D1 2017-04-28 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 RCV000077431 SCV001267450 uncertain significance Breast-ovarian cancer, familial 2 2017-12-19 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV000077431 SCV001481482 uncertain significance Breast-ovarian cancer, familial 2 2019-04-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a patient with breast or ovarian cancer [PMID 25556971]
Research and Development, ARUP Laboratories RCV001646762 SCV001852784 uncertain significance 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) RCV000077431 SCV000109229 uncertain significance Breast-ovarian cancer, familial 2 2012-01-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077431 SCV000147300 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 RCV001353878 SCV000592179 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Val2739Ile variant was identified in 10 of 3474 proband chromosomes (frequency: 0.003) from Australian, Polish, German and Hawaiian individuals or families with triple negative breast cancer or HBOC (Wong-Brown 2015 25682074, Lai 2015, Hondow 2011 21702907, Carney 2010 21218378, Trujillano 2015 25556971, Bosdet 2013 24094589). In a computational method that produces a probabilistic likelihood ratio predictive of impaired protein function, the variant was found to be neutral consistent with previously reported functional data related to homology directed repair (Karchin 2008). The variant was also identified in dbSNP (ID: rs80359069) “With Likely benign, Uncertain significance, other allele”, ClinVar (classified benign by Invitae, likely benign by Ambry Genetics, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Laboratory Corporation of America, SCRP and BIC), Clinvitae (5x), LOVD 3.0 (10x as predicted neutral and unknown function), UMD-LSDB (13x unclassified), BIC Database (6x unknown clinical importance, classification pending), and was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244404 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), in the East Asian population in 2 of 17246 chromosomes (freq: 0.0001), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish and South Asian populations. The p.Val2739 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the p.Val2739Ile variant impacting the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000045453 SCV001905871 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000045453 SCV001958988 likely benign not provided no assertion criteria provided clinical testing

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