ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.714_716dup (p.Ser239_Leu240insArg) (rs80359640)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214642 SCV000275210 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Insufficient evidence
Invitae RCV000234496 SCV000283308 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-02 criteria provided, single submitter clinical testing This sequence change inserts 3 nucleotides in exon 9 of the BRCA2 mRNA (c.714_716dupAAG). This leads to the insertion of 1 amino acid residue in the BRCA2 protein (p.Glu238_Ser239insArg) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs587778130, ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer, who had been tested for Lynch syndrome (PMID: 28195393). ClinVar contains and entry for this variant (Variation ID: 126202). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the inserted amino acid is currently unknown. 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.
GeneDx RCV000586365 SCV000568995 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This in-frame duplication of 3 nucleotides in BRCA2 is denoted c.714_716dupAAG at the cDNA level and p.Glu238_Ser239insArg (E238_S239insR) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 713_714insAAG or 942_944dupAAG. The normal sequence, with the bases that are duplicated in brackets, is ATGA[dupAAG]TCTG. This variant has been observed in an individual with familial colorectal cancer (Hansen 2017). This variant was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This insertion of a single Arginine amino acid is not located in a known functional domain. Since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Glu238_Ser239insArg to be a variant of uncertain significance.
Color RCV000214642 SCV000689032 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120386 SCV000695042 uncertain significance not specified 2020-07-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.714_716dupAAG (p.Glu238_Ser239insArg) results in an in-frame insertion that is predicted to insert one amino acids into the encoded protein. The variant allele was found at a frequency of 8e-06 in 250512 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.714_716dupAAG has been reported in the literature in individuals affected with ovarian cancer and colorectal cancer (Alsop_2012, Hansen_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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 RCV000586365 SCV000887902 uncertain significance not provided 2018-08-20 criteria provided, single submitter clinical testing
ITMI RCV000120386 SCV000084538 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000114068 SCV000147571 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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