ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.663T>G (p.Phe221Leu) (rs80358891)

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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 RCV000132202 SCV000187284 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031640 SCV000147440 uncertain significance Breast-ovarian cancer, familial 2 2000-07-07 no assertion criteria provided clinical testing
GeneDx RCV000759646 SCV000329131 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.663T>G at the cDNA level, p.Phe221Leu (F221L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). Using alternate nomenclature, this variant would be defined as BRCA2 c.891T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Phe221Leu 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 Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Phe221Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Phe221Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781125 SCV000918973 uncertain significance not specified 2018-07-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.663T>G (p.Phe221Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239668 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.663T>G has been reported in the literature in an at high risk for breast cancer (Lu_2012). This report 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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 RCV000759646 SCV000889108 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031640 SCV000054247 pathogenic Breast-ovarian cancer, familial 2 2009-02-03 no assertion criteria provided clinical testing

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