ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6531_6534del (p.Ile2177fs) (rs397507865)

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Total submissions: 7
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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) RCV000241269 SCV000301062 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000225746 SCV000072990 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile2177Metfs*13) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with a personal or family history of breast and/or ovarian cancer (PMID: 21913181, 29446198). This variant is also known as 6759del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 52122). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000044977 SCV000210783 pathogenic not provided 2014-02-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.6531_6534delTCAT at the cDNA level and p.Ile2177MetfsX13 (I2177MfsX13) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAT[delTCAT]GTTT. The deletion causes a frameshift, which changes an Isoleucine to a Methionine at codon 2177, and creates a premature stop codon at position 13 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.6531_6534delTCAT, previously reported as BRCA2 6759del4 using alternate nomenclature, has been published as a deleterious variant found in an individual with a personal history of breast cancer and family history of breast or ovarian cancer (Litton 2012).
Ambry Genetics RCV000221260 SCV000278575 pathogenic Hereditary cancer-predisposing syndrome 2016-09-16 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 RCV000241269 SCV000327452 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000225746 SCV000494295 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-08 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6531_6534delTCAT (p.Ile2177MetfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.6566dupA (p.Asn21869fsX8), c.6591_6592delTG (p.Glu2198fsX4), and c.6600_6601delTT (p.Ser2201X)). The variant was absent in 238302 control chromosomes (gnomAD). c.6531_6534delTCAT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Litton_2012, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044977 SCV000600709 pathogenic not provided 2016-12-14 criteria provided, single submitter clinical testing

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