ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2461G>A (p.Val821Ile) (rs756411508)

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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 RCV000564932 SCV000668762 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
CSER _CC_NCGL, University of Washington RCV000590888 SCV000700126 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-10-01 criteria provided, single submitter research Found in a 43 year old female patient having exome sequencing for an unrelated indication. No history of breast or ovarian cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Invitae RCV000590888 SCV000836077 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 821 of the BRCA2 protein (p.Val821Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs756411508, ExAC 0.01%). This variant has been observed in an individual affected with a personal and/or family history of breast and/or ovarian cancer. ClinVar contains an entry for this variant (Variation ID: 483080). 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 isoleucine 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.
Color Health, Inc RCV000564932 SCV000906040 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354575 SCV001549223 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 p.Val821Ile variant was identified in 1 of 1596 proband chromosomes (frequency: 0.0006) from individuals or families with hereditary breast and ovarian cancer and was present in 2 of 24980 control chromosomes (frequency: 0.00008) from healthy individuals (Park 2017, Momozawa 2018). The variant was also identified in dbSNP (ID: rs756411508) as "With Uncertain significance allele", in ClinVar (3x as Uncertain significance by Invitae and two other submitters, 1x as likely benign by Ambry Genetics), LOVD 3.0, and in the UMD-LSDB (2 records of unknown clinical significance) database. It was also identified in control databases in 2 of 242648 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111180 chromosomes (freq: 0.000009) and East Asian in 1 of 17926 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish or South Asian populations. The p.Val821 residue 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 variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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. This variant is classified as a variant of uncertain significance.

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