ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8414_8416delinsC (p.Leu2805fs) (rs397507402)

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Total submissions: 6
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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) RCV000031742 SCV000301275 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000219789 SCV000278778 pathogenic Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031742 SCV000327890 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000459143 SCV000549758 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides and inserts 1 nucleotide in exon 19 of the BRCA2 mRNA (c.8414_8416delinsC), causing a frameshift at codon 2805. This creates a premature translational stop signal (p.Leu2805Serfs*6) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). A set of variants that result in a similar protein effect have been reported in the literature in an individual affected with early-onset breast cancer. In this individual, two variants were described - a frameshift, c.8415_8416delAT (called 8643delAT), and a missense, c.8416T>C (called T8642C). If these two variants are in cis, they would result in the same variant observed here (c.8414_8416delinsC). However, the phase of these variants was not determined in the reported individual (PMID: 12942367). ClinVar contains an entry for this variant (Variation ID: 38159). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000486073 SCV000566482 pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA2 c.8414_8416delTATinsC at the cDNA level and p.Leu2805SerfsX6 (L2805SfsX6) at the protein level. The normal sequence, with the bases that are inserted in brackets, is CCCT[delTAT][insC]CATC. The variant causes a frameshift which changes a Leucine to a Serine at codon 2805, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.8414_8416delTATinsC, also reported as BRCA2 8642del3insC, has been reported in a male with a personal history of prostate, breast, and gastrointestinal stromal tumors and a family history of male and female breast cancer (Waisbren 2015). We consider this variant to be pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031742 SCV000054349 pathogenic Breast-ovarian cancer, familial 2 2008-10-12 no assertion criteria provided clinical testing

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