Submissions for variant NM_000059.4(BRCA2):c.772C>T (p.Gln258Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358998

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077409	SCV000300359	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045296	SCV000073309	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52395). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 22144684). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln258*) 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	RCV000131846	SCV000186901	pathogenic	Hereditary cancer-predisposing syndrome	2013-10-03	criteria provided, single submitter	clinical testing	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077409	SCV000327720	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045296	SCV002511788	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.772C>T (p.Gln258X) 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. The variant was absent in 250522 control chromosomes. c.772C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004566838	SCV005059098	pathogenic	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077409	SCV000109207	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-08-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077409	SCV000145712	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045296	SCV000587571	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research