ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5869A>G (p.Ile1957Val) (rs80358817)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203620 SCV000072793 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1957 of the BRCA2 protein (p.Ile1957Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs80358817, ExAC 0.002%). This variant has been reported in an individual who underwent testing for BRCA1 and BRCA2 germline variants (PMID: 21702907), and an individual affected with hereditary breast and ovarian cancer (PMID: 27376475). ClinVar contains an entry for this variant (Variation ID: 51957) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000129497 SCV000184269 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000044780 SCV000210620 likely benign not specified 2018-02-19 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.
Counsyl RCV000113498 SCV000487780 uncertain significance Breast-ovarian cancer, familial 2 2015-11-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513016 SCV000608681 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044780 SCV000694909 uncertain significance not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5869A>G (p.Ile1957Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict that this variant may have an impact on normal splicing by creating a 5' cryptic donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 250986 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5869A>G has been reported in the literature, without strong evidence for causality (Schenkel_2016). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely benign and 5x uncertain significance). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000513016 SCV000883508 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing The BRCA2 c.5869A>G; p.Ile1957Val variant (rs80358817) has been reported in at least one individual affected with hereditary breast and ovarian cancer (Schenkel 2016). It is reported as a variant of unknown significance by several laboratories in ClinVar (Variation ID: 51957) and observed in the European population at an overall frequency of 0.004% (5/126572) in the Genome Aggregation Database. The isoleucine at codon 1957 and computational algorithms (PolyPhen-2, SIFT) predict that this variant does not affect protein structure and/or function. Splice predictors (Alamut v.2.11) predict that this variant creates a cryptic donor splice site, but functional mRNA studies are necessary to determine the effect of this variant on splicing. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Schenkel L et al. Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. J Mol Diagn. 2016 Sep;18(5):657-667.
Color RCV000129497 SCV000903087 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113498 SCV000146720 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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