ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1103C>A (p.Ser368Ter) (rs80358407)

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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) RCV000112879 SCV000300385 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 RCV000043738 SCV000071751 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser368*) 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 the literature in an individual with a personal or family history of breast or ovarian cancer (PMID: 24156927). ClinVar contains an entry for this variant (Variation ID: 51064). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000258963 SCV000210262 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1103C>A at the cDNA level and p.Ser368Ter (S368X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 1331C>A. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in an individual with hereditary breast and ovarian cancer (Tea 2014). We consider this variant to be pathogenic.
Ambry Genetics RCV000222511 SCV000277253 pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112879 SCV000296673 pathogenic Breast-ovarian cancer, familial 2 2015-05-08 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112879 SCV000326496 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043738 SCV000591727 pathogenic Hereditary breast and ovarian cancer syndrome 2013-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000043738 SCV000694508 pathogenic Hereditary breast and ovarian cancer syndrome 2019-06-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1103C>A (p.Ser368X) 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 was absent in 249768 control chromosomes (gnomAD). c.1103C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lebo_2018, Rebbeck_2018, Tea_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different nucleotide change at the same position as the variant of interest (c.1103C>G) resulting in the same nonsense change (p.Ser368X) has been classified as pathogenic by our laboratory. Seven ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic (evaluations after 2014). Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000222511 SCV000905002 pathogenic Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112879 SCV000145813 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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