ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.632-3C>G (rs568027879)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000238832 SCV001161568 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.991879
Invitae RCV000204368 SCV000260035 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-28 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs568027879, ExAC 0.02%). This variant has been reported in an individual with a personal and/or family history of breast cancer (PMID: 22505045). ClinVar contains an entry for this variant (Variation ID: 219896). An experimental study using a patient's lymphoblastoid cell line has shown that this intronic change disrupts mRNA splicing (PMID: 22505045). 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.
Ambry Genetics RCV000220060 SCV000278028 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000766853 SCV000568450 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.632-3C>G or IVS7-3C>G and consists of a C>G nucleotide substitution at the -3 position of intron 7 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 860-3C>G. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. Additionally, RNA analysis of a patient lymphoblastoid cell line reportedly revealed that this variant creates a cryptic splice acceptor site; however, the native splice site remains intact (Houdayer 2012). It is unclear what effect this variant would have on the mRNA and resultant protein product. BRCA2 c.632-3C>G has been observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Houdayer 2012). BRCA2 c.632-3C>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA2 c.632-3C>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481337 SCV000600695 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing
Color RCV000220060 SCV001353618 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238832 SCV000297541 likely pathogenic Breast-ovarian cancer, familial 2 2011-12-06 no assertion criteria provided clinical testing

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