Submissions for variant NM_000059.3(BRCA2):c.1261C>T (p.Gln421Ter) (rs80358419)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112900	SCV000300413	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	RCV000131850	SCV000186905	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-19	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112900	SCV000326528	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000496684	SCV000918929	pathogenic	Hereditary breast and ovarian cancer syndrome	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1261C>T (p.Gln421X) 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.1265delA (p.Asn422fsX8), c.1310_1313delAAGA (p.Lys437fsX22), and c.1456C>T (p.Gln486X)). The variant was absent in 240472 control chromosomes (gnomAD). The variant, c.1261C>T, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Kwong_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112900	SCV000145842	not provided	Breast-ovarian cancer, familial 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000496684	SCV000587588	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research