ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.623T>G (p.Val208Gly) (rs80358865)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166634 SCV000217438 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113900 SCV000147315 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000166634 SCV000906878 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
Counsyl RCV000113900 SCV000785087 uncertain significance Breast-ovarian cancer, familial 2 2017-04-10 criteria provided, single submitter clinical testing
GeneDx RCV000759636 SCV000321447 uncertain significance not provided 2016-07-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.623T>G at the cDNA level, p.Val208Gly (V208G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant, also known as BRCA2 851T>G using alternate nomeclature, has been observed in at least two individuals with breast cancer (Nakamura 2013, Park 2016). BRCA2 Val208Gly was not associated with increased exon skipping in a minigene assay (Di Giacomo 2013). An adjacent missense variant, Thr207Ala, was predicted to alter the phosphorylation of BRCA2 (Tram 2013). BRCA2 Val208Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Glycine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val208Gly occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Val208Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781149 SCV000919019 uncertain significance not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.623T>G (p.Val208Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245698 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.1e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.623T>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Nakamura_2013, Arai_2018, Kim_2017, Takeuchi_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication showed that this variant is not associated with a splicing pattern consistent with exon 7 skipping (DiGiacomo_2013). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759636 SCV000889091 uncertain significance not provided 2018-06-12 criteria provided, single submitter clinical testing

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