Submissions for variant NM_000059.4(BRCA2):c.708T>C (p.His236=)

gnomAD frequency: 0.00002  dbSNP: rs185506536

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495426	SCV000579132	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics	RCV000163130	SCV000213643	likely benign	Hereditary cancer-predisposing syndrome	2014-10-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082184	SCV000261849	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735601	SCV000324850	likely benign	Breast and/or ovarian cancer	2016-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000436215	SCV000515798	benign	not specified	2015-04-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000436215	SCV000593699	likely benign	not specified	2016-02-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163130	SCV000683850	likely benign	Hereditary cancer-predisposing syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436215	SCV000695037	likely benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.708T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 275394 control chromosomes (gnomAD and Momozawa 2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.708T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven other submitters including one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x) / likely benign (6x). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587408	SCV000887900	likely benign	not provided	2023-02-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587408	SCV002048399	likely benign	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163130	SCV002531835	likely benign	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	curation
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735601	SCV000863739	uncertain significance	Breast and/or ovarian cancer	2014-05-26	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587408	SCV001951353	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587408	SCV001968497	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535065	SCV004709812	likely benign	BRCA2-related disorder	2023-03-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).