ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9891_9894dup (p.Gln3299fs) (rs730881619)

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Total submissions: 5
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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) RCV000241133 SCV000301419 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160313 SCV000210804 pathogenic Familial cancer of breast 2013-12-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9894_9895insATTT (aka c.9891_9894dupATTT) at the cDNA level and p.Gln3299IlefsX29 (Q3299IfsX29) at the protein level. The normal sequence with the bases that are duplicated in brackets is AGGC{ATTT}CAGC. The duplication causes a frameshift, changing a Glutamine to an Isoleucine at codon 3299, and creating a premature stop codon at position 29 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is considered pathogenic and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA1-BRCA2 panel(s).
Ambry Genetics RCV000222723 SCV000278644 pathogenic Hereditary cancer-predisposing syndrome 2017-04-10 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)
Invitae RCV000470171 SCV000549722 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-16 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotide in exon 27 of the BRCA2 mRNA (c.9891_9894dupATTT), causing a frameshift at codon 3299. This creates a premature translational stop signal in the last exon of the BRCA2 mRNA (p.Gln3299Ilefs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated BRCA2 protein. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 182326). This variant is expected to partially affect the amino acid residues Ala3270-Gly3305, which are critical for RAD51-mediated DNA repair activity of the BRCA2 protein (PMID: 17515903). A downstream truncating variant, p.Tyr3308*, has been observed in individuals with breast and/or ovarian cancer (PMID: 17026620, 22711857), and the deleterious effect of p.Tyr3308* has been well-established in cell-based model systems (PMID: 18593900, 18607349). This suggests that this variant is also deleterious to BRCA2 protein function. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759697 SCV000889195 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing

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