ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4258del (p.Asp1420fs) (rs80359436)

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Total submissions: 12
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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) RCV000077322 SCV000300729 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000165445 SCV000216175 pathogenic Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing The c.4258delG pathogenic mutation<span style="background-color:initial"> is <span style="background-color:initial">located in coding exon 10 of the BRCA2<span style="background-color:initial"> gene. This results from a deletion of one nucleotide at nucleotide position 4258, causing a translational frameshift with a predicted alternate stop codon (p.D1420Ifs*28). This mutation has been reported in two u<span style="background-color:initial">nrelated Scandinavian families with histories of breast, cervical, and pancreatic cancers, as well as in tumor tissue from three unrelated males diagnosed with breast cancer (H&aring;kansson S et al. Am J Hum Genet. 1997 May;60(5):1068-78). The <span style="background-color:initial">c.4258delG pathogenic mutation is commonly found in the <span style="background-color:initial">Swedish population and has been reported as a Swedish founder mutation (Janavičius R. EPMA J.<span style="background-color:initial"> 2010 Sep;1(3):397-412). Of note, this mutation is also designated as <span style="background-color:initial">4486delG. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000077322 SCV000220817 likely pathogenic Breast-ovarian cancer, familial 2 2014-10-20 criteria provided, single submitter literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077322 SCV000326996 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000077322 SCV000605650 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000657225 SCV000778951 pathogenic not provided 2017-07-05 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.4258delG at the cDNA level and p.Asp1420IlefsX28 (D1420IfsX28) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAAA[delG]ATTT. The deletion causes a frameshift which changes an Aspartic Acid to an Isoleucine at codon 1420, and creates a premature stop codon at position 28 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.4258delG has been observed in association with breast cancer and is known to be a pathogenic founder variant in the Swedish population (Hakansson 1997, Haraldsson 1998, Loman 2001, Janavicius 2010). We consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999883 SCV000883495 pathogenic not specified 2018-08-06 criteria provided, single submitter clinical testing The BRCA2 c.4258delG; p.Asp1420fs variant (rs80359436), also known as 4486delG, is reported in the literature in families with breast cancer (Hakansson 1997, Winter 2016), and is commonly found in the Swedish population (Janavicius 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51617), and is observed in the general population with a low overall allele frequency of 0.0008% (2/240284 alleles) in the Genome Aggregation Database. This variant deletes a single nucleotide causing a frameshift, and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997 May;60(5):1068-78. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. Winter C et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol. 2016 Aug;27(8):1532-8.
Color Health, Inc RCV000165445 SCV000906907 pathogenic Hereditary cancer-predisposing syndrome 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000496923 SCV001585418 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp1420Ilefs*28) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with breast cancer (PMID: 9150154). This variant is also known as c.4486delG in the literature. ClinVar contains an entry for this variant (Variation ID: 51617). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077322 SCV000109119 pathogenic Breast-ovarian cancer, familial 2 2012-04-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077322 SCV000146396 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 RCV000496923 SCV000587706 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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