ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.280C>T (p.Pro94Ser) (rs80358531)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129340 SCV000184104 likely benign Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification
Invitae RCV000589736 SCV000218670 likely benign not provided 2019-02-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589736 SCV000228767 uncertain significance not provided 2014-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589736 SCV000296711 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing
GeneDx RCV000589736 SCV000321446 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.280C>T at the cDNA level, p.Pro94Ser (P94S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 508C>T. This variant has been observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). A cDNA-based functional assay determined that this variant did not demonstrate allelic imbalance (Caux-Moncoutier 2009). BRCA2 Pro94Ser was observed at an allele frequency of 0.015% (5/33576) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Pro94Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000254706 SCV000591672 uncertain significance not specified 2013-11-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000254706 SCV000694632 uncertain significance not specified 2019-01-17 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA2 c.280C>T (p.Pro94Ser) 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 allele was found at a frequency of 5.3e-05 in 246052 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.280C>T has been reported in the literature in individuals affected with breast or ovarian cancer and HBOC (Caux-Moncoutier_2009, Ortiz_2016, Maksimenko_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant have been reported (BRCA1 c.5266dup, p.Gln1756fsX74 in UMD database), providing supporting evidence for a benign role. This variant had no effect in a study assessing allelic imbalance as an indirect measure of the impact of out-of-frame defects leading to reductions in the levels of mutant mRNA cleared through NMD (Caux-Moncoutier 2009). This indirectly supports that this variant has no effect on splicing. However, it is still possible that this variant can have effect on protein function by other mechanisms. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 as VUS, 2 as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000168018 SCV000838726 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129340 SCV000910810 likely benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000031384 SCV001138950 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031384 SCV000053989 benign Breast-ovarian cancer, familial 2 2012-03-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031384 SCV000146497 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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