ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1238del (p.Leu413fs) (rs80359271)

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Total submissions: 10
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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) RCV000031312 SCV000282354 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131980 SCV000187038 pathogenic Hereditary cancer-predisposing syndrome 2018-02-22 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)
GeneDx RCV000497276 SCV000210712 pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.1238delT at the cDNA level and p.Leu413HisfsX17 (L413HfsX17) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCCC[delT]ATTG. The deletion causes a frameshift which changes a Leucine to a Histidine at codon 413, and creates a premature stop codon at position 17 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.1238delT, also known as 1466delT using alternate nomenclature, has been reported in at least three individuals with breast cancer (Capalbo 2006, Giannini 2006, Caux-Moncoutier 2011). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031312 SCV000326523 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496247 SCV000694524 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1238delT (p.Leu413Hisfs) variant (alternatively also known as 1466delT) 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.Ser1630X, p.Tyr1739X, p.Asn1747X). This variant is absent in 120730 control chromosomes from ExAC. This variant has been reported in several HBOC patients/families in literature and clinical databases. In addition, several clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Color RCV000131980 SCV000903392 pathogenic Hereditary cancer-predisposing syndrome 2014-11-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778390 SCV000914619 pathogenic BRCA2-Related Disorders 2019-01-13 criteria provided, single submitter clinical testing The BRCA2 c.1238delT (p.Leu413HisfsTer17) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu413HisfsTer17 has been reported in eight studies in which it has been identified in a heterozygous state in at least 11 individuals with hereditary cancer, either breast cancer, breast cancer and ovarian cancer or ovarian cancer alone (Capalbo et al. 2006; Giannini et al. 2006; Caux-Moncoutier et al. 2011; Concolino et al.2014; Coppa et al. 2014; Minucci 2015; Manie et al. 2016; Palmero et al. 2018). The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Although the c.3201+1G>C variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Based on the evidence and the potential impact of frameshift variants, the BRCA2 p.Leu413HisfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Sharing Clinical Reports Project (SCRP) RCV000031312 SCV000053917 pathogenic Breast-ovarian cancer, familial 2 2014-01-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031312 SCV000145838 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496247 SCV000587586 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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