ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1755_1759del (p.Lys585fs) (rs80359302)

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Total submissions: 14
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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) RCV000031335 SCV000300459 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 RCV000074514 SCV000071887 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys585Asnfs*3) 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 individuals affected with breast and/or ovarian cancer (PMID: 15131399, 16284991, 20616022, 19620486, 25186627), and individuals with breast, pancreatic, and fallopian tube cancer (PMID: 26681312). This variant is also known as 1983del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 37754). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000212215 SCV000108599 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.1755_1759delGAAAA at the cDNA level and p.Lys585AsnfsX3 (K585NfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAAAA[delGAAAA]CAAA. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 585, and creates a premature stop codon at position 3 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.1755_1759delGAAAA, also known as 1983del5 using alternative nomenclature, has been reported in individuals with a personal and/or family history of breast, ovarian, and pancreatic cancer (Lubinski 2004, Pal 2005, Couch 2007, Watson 2009, Senter 2014). We consider this variant to be pathogenic.
Ambry Genetics RCV000131055 SCV000185985 pathogenic Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000131055 SCV000292147 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212215 SCV000296726 pathogenic not provided 2015-02-17 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031335 SCV000326603 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031335 SCV000489106 pathogenic Breast-ovarian cancer, familial 2 2016-08-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212215 SCV000885084 pathogenic not provided 2017-07-18 criteria provided, single submitter clinical testing The BRCA2 c.1755_1759del, p.Lys585fs variant (rs80359302) has been reported in a family with breast and/or ovarian cancer (Lubinski 2004). It is listed in ClinVar as pathogenic (Variation ID: 37754), and observed in the general population databases at a very low frequency (1/245304 alleles; Genome Aggregation Database). The variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. REFERENCES Link to ClinVar database for c.1755_1759del: https://www.ncbi.nlm.nih.gov/clinvar/variation/37754/ Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10.
Illumina Clinical Services Laboratory,Illumina RCV000778391 SCV000914620 pathogenic BRCA2-Related Disorders 2018-10-18 criteria provided, single submitter clinical testing The BRCA2 c.1755_1759delGAAAA (p.Lys585AsnfsTer3) variant, also known as 1983del5 results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys585AsnfsTer3 variant has been reported in at least three studies in which it is found in a heterozygous state in a total of eight patients diagnosed with breast, ovarian/fallopian tube, pancreatic, or other cancers (Lubinski et al. 2004; Pal et al. 2005; Susswein et al. 2016). The p.Lys585AsnfsTer3 variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Hall et al. (2016) developed a mouse model of pancreatic acinar cell carcinoma and determined that it was homozygous for the BRCA2 p.Lys585AsnfsTer3 variant. Immunohistochemical staining of tissues from this mouse model revealed that the mutated BRCA2 protein was not localized to the nucleus, but was instead only expressed in the cytoplasm, as compared to normal tissues where BRCA2 was localized to both the nucleus and cytoplasm. This variant has not been reported in the literature in association with Fanconi anemia, and this variant could not be ruled out of causing this disease based on based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode. Due to the potential impact of frameshift variants, the p.Lys585AsnfsTer3 variant is classified as pathogenic for BRCA2-related disorders.
Integrated Genetics/Laboratory Corporation of America RCV000074514 SCV000916840 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1755_1759delGAAAA (p.Lys585AsnfsX3) 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.1763_1766delATAA, p.Asn588fsX25; c.1796_1800delCTTAT, p.Ser599X; c.1800T>A, p.Tyr600X). The variant allele was found at a frequency of 4.1e-06 in 245304 control chromosomes (gnomAD). c.1755_1759delGAAAA has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer, fallopian tube cancer and pancreatic cancer (Susswein_2016, Senter_2014, Pal_2005, Lubinski_2004). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031335 SCV000053940 pathogenic Breast-ovarian cancer, familial 2 2011-12-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031335 SCV000145926 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 RCV000074514 SCV000587607 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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