ClinVar Miner

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

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Total submissions: 8
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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 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-05 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 observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 22505045). ClinVar contains an entry for this variant (Variation ID: 219896). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22505045, 30883759). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000220060 SCV000278028 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing The c.632-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 7 in the BRCA2 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site and create a new splice acceptor site. This alteration results in use of this novel cryptic acceptor site two nucleotides upstream of the native site resulting in a frameshifting transcript (Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Fraile-Bethencourt E et al. J. Pathol., 2019 08;248:409-420). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 Health, Inc RCV000220060 SCV001353618 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-19 criteria provided, single submitter clinical testing This variant causes a C to G nucleotide substitution at the -3 position of intron 7 of the BRCA2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Functional RNA studies have shown that this variant causes the use of an alternative splice acceptor site 2-nucleotide upstream of the reference acceptor site, creating premature translation stop signal in the RNA transcripts (PMID: 22505045, 30883759). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22505045, Color internal data). In addition, a multifactorial likelihood model using health history and tumor pathology data has suggested this variant have a high probability of being pathogenic (PMID: 31131967). This variant has been identified in 1/243142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Research and Development, ARUP Laboratories RCV001640309 SCV001854335 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2017-02-01 criteria provided, single submitter curation
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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