Submissions for variant NM_000059.4(BRCA2):c.3839A>T (p.Asp1280Val)

gnomAD frequency: 0.00007  dbSNP: rs56337919

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077315	SCV000244442	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000286
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080923	SCV000072291	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000587147	SCV000210597	likely benign	not provided	2020-12-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24323938, 11698567, 17924331, 21990134)
Ambry Genetics	RCV000162783	SCV000213261	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Counsyl	RCV000077315	SCV000487915	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044278	SCV000694722	benign	not specified	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3839A>T (p.Asp1280Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 212168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3839A>T has been reported in the literature in sequencing studies of individuals with high risk breast cancer as well as in an unaffected individual (Lu_2012, Carney_2010) in addition to sequencing studies of patients undergoing cancer screening for varied indications (example, Easton_2007, DeLeeneer_2008, Seymour_2008, Hartman_2001, Machackova_2019). These reports do not provide unequivocal conclusions regarding the association of this variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.66dupA, p.Glu23fsX18), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=4)/likely benign(n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. We have not identified any evidence supporting an actionable outcome in over 5 years since its initial classification by our laboratory. Based on the evidence outlined above, and the predominant consensus in the field, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000587147	SCV000805700	likely benign	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162783	SCV000902727	benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000044278	SCV002070437	likely benign	not specified	2021-12-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162783	SCV002533823	likely benign	Hereditary cancer-predisposing syndrome	2020-12-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044278	SCV002550325	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077315	SCV000109112	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-10-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077315	SCV000146306	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077315	SCV004243611	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing