ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3451A>G (p.Ile1151Val) (rs80358591)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044197 SCV000072210 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1151 of the BRCA2 protein (p.Ile1151Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs80358591, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51467). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000214609 SCV000277208 likely benign Hereditary cancer-predisposing syndrome 2017-03-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000214609 SCV000906682 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502245 SCV000916861 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3451A>G (p.Ile1151Val) alters a non-conserved nucleotide resulting in a conservative amino acid change in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3451A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113178 SCV000146236 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113178 SCV000297519 uncertain significance Breast-ovarian cancer, familial 2 2013-08-22 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000113178 SCV000591862 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Ile1151Val variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server: 1000 Genomes), HGMD, LOVD, COSMIC, GeneInsight, VariantWire and UMD. The variant is listed in the dbSNP database (rs80358591) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014)in 1 of 66654 individuals from a population of European (Non-Finnish) and not found in East Asian, African, Latino, South Asian, European (Finnish) or Other individuals, The variant was identified in the BIC database (1X with unknown clinical importance); the ClinVar database (classified as a Uncertain significance by BIC and no classification was provided by Invitae). The p.Ile1151residue is not conserved in mammals and 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 p.Ile1151Val 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. 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 unknown significance.

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