ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4631del (p.Asn1544fs) (rs80359460)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160290 SCV000602866 pathogenic not provided 2017-11-21 criteria provided, single submitter clinical testing The BRCA2 c.4631delA, p.Asn1544fs variant (rs80359461) has been reported in patients diagnosed with early-onset breast cancer (Hopper 1999) or invasive ovarian cancer (Zhang 2011). It is listed as pathogenic in ClinVar (Variation ID: 37913), and observed once in the Genome Aggregation Database general population database (1/245410 alleles). 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: Hopper J et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999; 8(9):741-7. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7.
Ambry Genetics RCV000130639 SCV000185518 pathogenic Hereditary cancer-predisposing syndrome 2018-04-19 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031494 SCV000146459 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044455 SCV000586954 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000130639 SCV000683638 pathogenic Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031494 SCV000327061 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031494 SCV000221090 pathogenic Breast-ovarian cancer, familial 2 2015-01-28 criteria provided, single submitter literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044455 SCV000591916 pathogenic Hereditary breast and ovarian cancer syndrome 2013-11-08 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031494 SCV000300773 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160290 SCV000210754 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.4631delA at the cDNA level and p.Asn1544ThrfsX24 (N1544TfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAA[delA]CCTT. The deletion causes a frameshift, which changes an Asparagine to a Threonine at codon 1544, and creates a premature stop codon at position 24 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.4631delA, also known as 4859delA using alternate nomenclature, has been observed in women with breast and/or ovarian cancer and has also been described as a founder pathogenic variant in the Philippines (Risch 2001, De Leon-Matsuda 2002, Zhang 2011). We consider this variant to be pathogenic.
GeneKor MSA RCV000160290 SCV000296822 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044455 SCV000694788 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was observed in the large, broad control population, ExAC, 1/120458, although this observance needs to be cautiously considered due to the cohort harboring individuals with a phenotype that could harbor a BRCA2 mutation. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, the variant of interest is classified as Pathogenic.
Invitae RCV000044455 SCV000072468 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1544Thrfs*24) 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 as well as non-Hodgkin's lymphoma (PMID: 10498392, 21324516, 11920621), and is a common cause of breast cancer in individuals of Filipino ancestry (PMID: 11920621, 17591843). This variant is also known as 4856delA and 4859delA in the literature. ClinVar contains an entry for this variant (Variation ID: 37913). 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 RCV000160290 SCV000296675 pathogenic not provided 2015-05-13 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044455 SCV000587719 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031494 SCV000054099 pathogenic Breast-ovarian cancer, familial 2 2014-03-12 no assertion criteria provided clinical testing

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