Submissions for variant NM_000059.4(BRCA2):c.1945C>T (p.Gln649Ter)

dbSNP: rs398122735

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077672	SCV000300479	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077672	SCV000326639	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077672	SCV000605628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772116	SCV000905177	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with DCIS (PMID: 28423363) and has been identified in 3 families among the CIMBA participants (PMID: 29446198). 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.
Invitae	RCV000496928	SCV001218302	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 91764). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28423363, 29339979, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln649*) 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). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262845	SCV001440868	pathogenic	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496928	SCV001467882	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1945C>T (p.Gln649X) 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 240878 control chromosomes (gnomAD). c.1945C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome as well as in individuals undergoing testing (Rebbeck_2018, Heramb_2018, Tedaldi_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000772116	SCV003995787	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.Q649* pathogenic mutation (also known as c.1945C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1945. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV001262845	SCV004212881	pathogenic	Familial cancer of breast	2021-11-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077672	SCV000109475	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-08-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496928	SCV000587620	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research