Submissions for variant NM_000059.3(BRCA2):c.3785C>G (p.Ser1262Ter) (rs80358620)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113219	SCV000282383	pathogenic	Breast-ovarian cancer, familial 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044266	SCV000072279	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1262*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80358620, ExAC 0.002%). This variant has been observed in an individual affected with ovarian cancer (PMID: 24728189). ClinVar contains an entry for this variant (Variation ID: 51525). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129108	SCV000183819	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-07	criteria provided, single submitter	clinical testing	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	RCV000113219	SCV000326915	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000481804	SCV000566129	pathogenic	not provided	2018-11-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3785C>G at the cDNA level and p.Ser1262Ter (S1262X) at the protein level. Using alternate nomenclature, this variant would be defined as 4013C>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 association with breast and ovarian cancer (Loughrey 2008, de Juan Jim?nez 2013, Song 2014). We consider this variant to be pathogenic.
Counsyl	RCV000113219	SCV000786273	pathogenic	Breast-ovarian cancer, familial 2	2018-04-02	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000044266	SCV000916867	pathogenic	Hereditary breast and ovarian cancer syndrome	2020-09-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3785C>G (p.Ser1262X) 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 allele was found at a frequency of 4.1e-06 in 245754 control chromosomes (gnomAD and publication data). c.3785C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Coulet_2010, Song_2014, Rebbeck_2018). 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. Ten ClinVar submitters (evaluation after 2014), including one expert panel (ENIGMA), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000113219	SCV000993559	pathogenic	Breast-ovarian cancer, familial 2	2019-05-23	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481804	SCV001133771	pathogenic	not provided	2019-02-22	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Color	RCV000129108	SCV001340013	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113219	SCV000146297	pathogenic	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113219	SCV000297522	pathogenic	Breast-ovarian cancer, familial 2	2012-04-30	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000129108	SCV000805241	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-09	no assertion criteria provided	clinical testing