ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5159C>A (p.Ser1720Ter) (rs80358740)

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Total submissions: 9
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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) RCV000238884 SCV000300835 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 RCV000131919 SCV000186974 pathogenic Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing The p.S1720* pathogenic mutation (also known as c.5159C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5159. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been reported in a patient with prostate cancer (Mandelker D et al. JAMA, 2017 09;318:825-835). 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.
Invitae RCV000459811 SCV000549735 pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1720 (p.Ser1720*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000131919 SCV000683677 pathogenic Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing
GeneDx RCV000657663 SCV000779412 pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5159C>A at the cDNA level and p.Ser1720Ter (S1720X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 5387C>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 at least one individual with advanced prostate cancer (Mandelker 2017) and is considered pathogenic.
Counsyl RCV000238884 SCV000786214 likely pathogenic Breast-ovarian cancer, familial 2 2018-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657663 SCV001133818 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Sharing Clinical Reports Project (SCRP) RCV000238884 SCV000297533 pathogenic Breast-ovarian cancer, familial 2 2009-10-27 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000238884 SCV000591946 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Ser1720X variant was identified in the Clinvar database with a pathogenic classification by Ambry Genetics. The variant was not identified in the literature, nor in any of the other databases searched (dbSNP, NHLBI Exome Sequencing Project (Exomae Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, BIC, LOVD, GeneInsight COGR database, or the UMD). The p.Ser1720X variant leads to a premature stop codon at position 1720, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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