ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5195del (p.Leu1732fs) (rs587779363)

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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 RCV000509598 SCV000607920 pathogenic Hereditary cancer-predisposing syndrome 2017-10-06 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)
Color RCV000509598 SCV000905013 pathogenic Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077349 SCV000327163 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077349 SCV000300842 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 RCV000074535 SCV000108620 pathogenic Familial cancer of breast 2013-09-25 no assertion criteria provided clinical testing This variant is denoted c.5195delT at the cDNA level or p.Leu1732ProfsX9 (L1732PfsX9) at the protein level. The sequence with the deleted bases in brackets is: CATC{T}CTCC. The deletion is a frameshift variant, changing a Leucine residue to a Proline residue at codon 1732, and creating a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this particular deletion has not been reported in the literature to our knowledge, its presence is consistent with the risk to develop features associated with Hereditary Breast and Ovarian Cancer syndrome. Hereditary Breast and Ovarian Cancer (HBOC) syndrome is 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 variants 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 variants also have an increased risk for contralateral breast cancer. Women with BRCA variants 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 variants 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 variants 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 variant 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 BRCA2 panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000781123 SCV000918971 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5195delT (p.Leu1732ProfsX9) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Thr1738fsX2, p.Tyr1739X, p.Asn1747X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 239694 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
PreventionGenetics RCV000679176 SCV000805717 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077349 SCV000109146 pathogenic Breast-ovarian cancer, familial 2 2011-07-26 no assertion criteria provided clinical testing

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