Submissions for variant NM_000059.4(BRCA2):c.9523G>T (p.Glu3175Ter)

dbSNP: rs397507430

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031829	SCV000301400	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Department of Medical Genetics, Oslo University Hospital	RCV000031829	SCV000605646	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000496351	SCV000836418	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 38246). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu3175*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).
Ambry Genetics	RCV002371800	SCV002688448	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	clinical testing	The p.E3175* variant (also known as c.9523G>T), located in coding exon 25 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9523. This changes the amino acid from a glutamic acid to a stop codon within coding exon 25. In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 1 family (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the information 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496351	SCV004121831	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9523G>T (p.Glu3175X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251358 control chromosomes (gnomAD). c.9523G>T has been reported in the literature in individuals affected with breast and-or ovarian cancer (e.g. Heramb_2018, Olafsdottir_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ENIGMA), have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031829	SCV000054437	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-18	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496351	SCV000588010	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483443	SCV004228896	not provided	BRCA2-Related Disorders		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 03-10-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.