Submissions for variant NM_000059.4(BRCA2):c.10150C>T (p.Arg3384Ter)

gnomAD frequency: 0.00001  dbSNP: rs397507568

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043720	SCV000071733	likely benign	Hereditary breast ovarian cancer syndrome	2023-08-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001719790	SCV000518277	likely benign	not provided	2018-03-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25863477, 17100994, 27882536, 29192238, 16949048, 20104584, 27157322, 22970155, 27701467, 28825143, 30720863, 30287823, 29446198, 31666926, 29625052)
Ambry Genetics	RCV000565885	SCV000661329	likely benign	Hereditary cancer-predisposing syndrome	2018-11-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000565885	SCV000688689	likely benign	Hereditary cancer-predisposing syndrome	2017-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000438903	SCV000918935	uncertain significance	not specified	2017-12-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.10150C>T (p.Arg3384X) variant results in truncation of the last 35 amino acids in the last exon; therefore it is unexpected to cause nonsense-mediated decay. Truncations downstream of this position have not been classified as pathogenic by our laboratory and others in ClinVar. This variant was found in 4/277292 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The BRCA2 c.9976A>T (p.Lys3326*) variant, located upstream of this variant and also in the last exon of the gene, is a known benign variant suggesting that the truncation of the last 93 amino acids of BRCA2 is unlikely to be pathogenic for breast and/or ovarian cancer. One individual reported in a database (UMD) carrying this variant also carried a premature truncating variant in BRCA1 c.2205delA (Glu736LysfsX17), further supporting for the benign outcome. This variant has been reported in several breast and/or ovarian cancer patients without strong evidence for or against pathogenicity (Han_2006, Borg_2010, Kwong_2012, Choi_2015, Kang_2015, Hayano_2016, Loizidou_2017, Kwong_2016, Zhang_2017, Yamaguchi-Kabata_2017). In one breast cancer patient carrying this variant, another missense variant in PALB2 variant was also detected (Zhang_2017). The publications classify this variant as pathogenic and uncertain significance. Multiple clinical diagnostic laboratories have recently classified this variant as likely benign (2) as well as uncertain significance (1). Taken together this variant is classified as Variant of Unknown Significance-Possibly Benign.
Mendelics	RCV000112844	SCV001139288	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565885	SCV002533194	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719790	SCV002774120	likely benign	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112844	SCV000145758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-20	no assertion criteria provided	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000043720	SCV000586995	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-14	no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677846	SCV000804006	uncertain significance	Malignant tumor of pancreas	2017-10-09	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250507	SCV002520852	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162361	SCV002758423	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Department of Medical and Surgical Sciences, University of Bologna	RCV000112844	SCV004228310	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)