ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3075_3076delinsTT (p.Lys1025_Lys1026delinsAsnTer) (rs587779362)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165145 SCV000215856 pathogenic Hereditary cancer-predisposing syndrome 2016-09-30 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 RCV000165145 SCV000688784 pathogenic Hereditary cancer-predisposing syndrome 2017-06-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000239127 SCV000326810 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) RCV000239127 SCV000324132 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000074523 SCV000108608 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3075_3076delGAinsTT at the cDNA level and p.Lys1025_Lys1026delinsAsnTer (K1025_K1026delinsNX) at the protein level. The surrounding sequence is TTAA[delGA][insTT]AGAG. The variant results in the replacement of a Lysine with an Asparagine residue at codon 1025 followed by a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.3075_3076delGAinsTT, also reported as two separate events (c.3075G>T, p.Lys1025Asn; c.3076A>T, p.Lys1026X), has been reported in at least four women with a personal and family history of breast and/or ovarian cancer (Pohlreich 2005, Wong-Brown 2015). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000205398 SCV000916863 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3075_3076delinsTT (p.Lys1025AsnfsX2) 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. c.3109C>T, p.Gln1037X; c.3166C>T, p.Gln1056X; c.3170_3174delAGAAA, p.Lys1057fsX8). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 245182 control chromosomes and has been reported in affected individuals in the literature (Pohlreich, 2005, Wong-Brown, 2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000205398 SCV000260670 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1025_Lys1026delinsAsn*) 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 reported in individuals affected with breast and ovarian cancer (PMID: 16168118, 25682074), and in an individual with increased risk of breast and ovarian cancers (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 89046). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000074523 SCV000778660 pathogenic not provided 2017-12-23 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239127 SCV000296536 pathogenic Breast-ovarian cancer, familial 2 2016-04-23 criteria provided, single submitter clinical testing

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