ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.235A>G (p.Ile79Val) (rs80358502)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561580 SCV000668684 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Color Health, Inc RCV000561580 SCV000911860 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031364 SCV000053969 uncertain significance Breast-ovarian cancer, familial 2 2008-01-31 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031364 SCV000146419 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500366 SCV000591666 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ile79Val variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Fanconi’s Anemia Mutation Database (LOVD), COSMIC, GeneInsight COGR, MutDB or ARUP . This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 3 of 121174 chromosomes (frequency: 2.05x10-5); all 3 were found in 6614 alleles (frequency: 4.54x10-4) in the European Finnish population, increasing the likelihood that this may be a low frequency benign variant. The variant was not identified in populations of South Asians, European (Non-Finnish), East Asian, African, Latino, and other individuals.The variant was also identified in dbSNP (ID: rs80358502 “With Uncertain significance allele”. The ClinVar database classified the variant as an uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports), as uncertain significance by BIC and classification not provided by Invitae. The variant was identified in BIC database (1x with Unknown clinical importance), and BRCA Share UMD (1x as an unknown variant). The p.Ile79 residue is not conserved in mammals and the variant amino acid Valine (Val) is present in Cows and African clawed frogs, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.235A>G variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a cryptic splice acceptor site. However, this information is not predictive enough to assume pathogenicity. 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 a variant of unknown significance.

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