ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9148C>T (p.Gln3050Ter) (rs80359170)

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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) RCV000083155 SCV000301355 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 RCV000221883 SCV000279199 pathogenic not provided 2015-12-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9148C>T at the cDNA level and p.Gln3050Ter (Q3050X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant, also known as 9376C>T using alternate nomenclature, has not been reported in the literature in association with breast or ovarian cancer, it is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083155 SCV000328068 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000083155 SCV000488214 likely pathogenic Breast-ovarian cancer, familial 2 2016-01-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771484 SCV000903963 pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771484 SCV001180210 pathogenic Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.Q3050* pathogenic mutation (also known as c.9148C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9148. This changes the amino acid from a glutamine to a stop codon within coding exon 23. 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 RCV001383878 SCV001583192 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln3050*) 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 individual(s) with hereditary breast and ovarian cancer syndrome (PMID: 29506128). ClinVar contains an entry for this variant (Variation ID: 52762). 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) RCV000083155 SCV000115229 pathogenic Breast-ovarian cancer, familial 2 2010-06-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083155 SCV000147552 pathogenic Breast-ovarian cancer, familial 2 2000-07-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000083155 SCV001550465 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Gln3050* variant was identified in 1 of 59400 proband chromosomes (frequency: 0.000016) in worldwide study of 29,700 families with BRCA1 or BRCA2 mutations (Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359170) as "With Pathogenic allele", ClinVar (classified as pathogenic by six submitters and likely pathogenic by one submitter), and LOVD 3.0 (2x as pathogenic). The variant was tested in comprehensive splicing functional analysis using bioinformatics analysis of putative splicing and showed minor splicing defects (Acedo 2012). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9148C>T variant leads to a premature stop codon at position 3050 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 BRCA2 associated cancers 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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