ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3170_3174del (p.Lys1057fs) (rs80359373)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131091 SCV000186021 pathogenic Hereditary cancer-predisposing syndrome 2018-04-05 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000031407 SCV000146184 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735538 SCV000901105 pathogenic Breast and/or ovarian cancer 2017-09-06 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044141 SCV000586939 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000131091 SCV000683533 pathogenic Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031407 SCV000326827 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031407 SCV000489135 pathogenic Breast-ovarian cancer, familial 2 2016-08-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044141 SCV000591849 pathogenic Hereditary breast and ovarian cancer syndrome 2014-02-11 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044141 SCV000588089 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031407 SCV000300594 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735538 SCV000863676 pathogenic Breast and/or ovarian cancer 2015-10-02 no assertion criteria provided clinical testing
GeneDx RCV000220190 SCV000278845 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.3170_3174delAGAAA at the cDNA level and p.Lys1057ThrfsX8 (K1057TfsX8) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAA[delAGAAA]CTGA. The deletion causes a frameshift, which changes a Lysine to a Threonine at codon 1057, and creates a premature stop codon at position 8 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.3170_3174delAGAAA, previously reported as BRCA2 3398del5, has been observed in families with hereditary breast and ovarian cancer and is considered a French Canadian pathogenic founder variant (Lubinski 2004, Oros 2006, Janavicius 2010, de Juan Jimenez 2013, Andrei 2015, Belanger 2015, Pritchard 2016). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031407 SCV000839918 pathogenic Breast-ovarian cancer, familial 2 2017-05-25 criteria provided, single submitter clinical testing The c.3170_3174del (p.Lys1057Thrfs*8) variant in the BRCA2 gene has been detected in one family from a cohort of cancer patients [PMID 15131399, reported as 3398delAAAAG] and a cohort of patients with prostate cancer [PMID 27433846]. The variant was also reported in 11 patients in the Breast Cancer Information Core database. This 5 bp deletion in exon 11 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has been detected in three individuals in the ExAC database (http://exac.broadinstitute.org/variant/13-32911658-CAAAAG-C). This variant thus classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044141 SCV000918996 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3170_3174delAGAAA (p.Lys1057ThrfsX8) 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. The variant allele was found at a frequency of 1.2e-05 in 241872 control chromosomes (gnomAD). c.3170_3174delAGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski_2004, Oros_2004, de Juan Jimenez_2013, Ghadirian_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000044141 SCV000072154 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1057Thrfs*8) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781096360, ExAC 0.005%). This variant has been reported as recurrent in French Canadian individuals and families with breast, ovarian, and pancreatic cancer (PMID: 15131399, 15382066, 16539696, 25864590, 20694749, 23621881). It has also been reported in individuals with breast and prostate cancer from other populations (PMID: 25863477, 26296701, 27433846). This variant is also known as 3398delAAAAG and 3398del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37826). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220190 SCV000296698 pathogenic not provided 2015-04-30 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044141 SCV000587662 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031407 SCV000054012 pathogenic Breast-ovarian cancer, familial 2 2013-01-31 no assertion criteria provided clinical testing

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