ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9041C>G (p.Ser3014Ter) (rs80359156)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000240993 SCV000301341 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 RCV000129551 SCV000184331 pathogenic Hereditary cancer-predisposing syndrome 2018-03-17 criteria provided, single submitter clinical testing The p.S3014* pathogenic mutation (also known as c.9041C>G), located in coding exon 22 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9041. This changes the amino acid from a serine to a stop codon within coding exon 22. This mutation was detected twice in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). 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.
GeneDx RCV000413054 SCV000490439 pathogenic not provided 2018-11-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9041C>G at the cDNA level and p.Ser3014Ter (S3014X) at the protein level. Using alternate nomenclature this variant would be defined as BRCA2 9269C>G. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), 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 who underwent whole exome sequencing, with no clinical phenotype information provided (LaDuca 2017). This variant is considered pathogenic.
Invitae RCV000559907 SCV000635712 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser3014*) 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 not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141162). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000559907 SCV000838889 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000559907 SCV000917065 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9041C>G (p.Ser3014X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.9076C>T (p.Gln3026X), c.9196C>T (p.Gln3066X), c.9294C>G (p.Tyr3098X)). The variant was absent in 245312 control chromosomes (gnomAD). c.9041C>G has been reported in the literature in individuals undergoing germline targeted NGS multi-gene panel testing . It is important to note, a variant at the same nucleotide position as the variant of interest which causes a different nucleotide change (c.9041C>A) but the same amino-acid change (p.S3014X) has been reported in individuals affected with Breast Cancer (Sun_2017) and it is cited in ClinVar as pathogenic. Five ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant of interest as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000129551 SCV001736142 pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. A similar variant (with a different nucleotide change but resulting in the same premature stop in exon 23) has been reported in individuals affected with breast cancer (PMID: 28724667). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.