ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2629C>G (p.Pro877Ala) (rs80358524)

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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 RCV000570550 SCV000661293 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113071 SCV000146082 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Counsyl RCV000113071 SCV000784784 uncertain significance Breast-ovarian cancer, familial 2 2017-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000483653 SCV000567343 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2629C>G at the cDNA level, p.Pro877Ala (P877A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 2857C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro877Ala was not observed 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Pro877Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780044 SCV000917061 uncertain significance not specified 2018-12-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2629C>G (p.Pro877Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 221836 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2629C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Invitae RCV000556749 SCV000635234 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 877 of the BRCA2 protein (p.Pro877Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 125989). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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