ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7507G>A (p.Val2503Ile) (rs587782191)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130837 SCV000185735 likely benign Hereditary cancer-predisposing syndrome 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Invitae RCV000459125 SCV000549651 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2503 of the BRCA2 protein (p.Val2503Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587782191, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22034289, 25802882, 29088781, 27741520), and a family affected with familial non-medullary thyroid cancer (PMID: 26530882). ClinVar contains an entry for this variant (Variation ID: 142036). 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. 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.
GeneDx RCV000479926 SCV000565719 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7507G>A at the cDNA level, p.Val2503Ile (V2503I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). Using alternate nomenclature, this variant would be defined as BRCA2 7735G>A. This variant was observed in individuals with breast, ovarian, or pancreatic cancer and in a patient with familial non-medullary thyroid cancer (Fackenthal 2012, Hirotsu 2015, Yu 2015, Fernandes 2016, Alvarez 2017, Kondo 2018). BRCA2 Val2503Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the FANCD2 binding domain (UniProt, Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val2503Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662953 SCV000785919 uncertain significance Breast-ovarian cancer, familial 2 2018-01-10 criteria provided, single submitter clinical testing
Color RCV000130837 SCV000911414 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779919 SCV000916845 uncertain significance not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7507G>A (p.Val2503Ile) results in a conservative amino acid change located in the helical domain (IPR015252, InterPro), that belongs to the BRCA2 DNA-binding domain. 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 246186 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.7507G>A variant has been reported in the literature in individuals affected with HBOC and non-medullary thyroid cancer (Hirotsu 2014, Fackenthal 2012, Fernandes 2016, Alvarez 2017), however these report(s) do not provide unequivocal conclusions about association of the variant with HBOC. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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.

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