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
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.
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
Breast Cancer Information Core (BIC) (BRCA2) RCV000113498 SCV000146720 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513016 SCV000608681 uncertain significance not provided 2017-04-30 criteria provided, single submitter clinical testing
Color RCV000129497 SCV000903087 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000113498 SCV000487780 uncertain significance Breast-ovarian cancer, familial 2 2015-11-21 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000513016 SCV000694909 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5869A>G (p.Ile1957Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120992 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature, without strong evidence for causality. While one clinical diagnostic laboratory has classified the variant as likely benign (without evidence to independently evaluate), multiple other clinical diagnostic laboratories/databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000203620 SCV000072793 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-26 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.

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