Submissions for variant NM_000059.3(BRCA2):c.4494T>A (p.Gly1498=) (rs373160367)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000494989	SCV000578744	likely benign	Breast-ovarian cancer, familial 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	RCV000163657	SCV000214227	likely benign	Hereditary cancer-predisposing syndrome	2014-09-18	criteria provided, single submitter	clinical testing
Invitae	RCV000226722	SCV000283239	likely benign	Hereditary breast and ovarian cancer syndrome	2017-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000426463	SCV000517852	likely benign	not specified	2018-02-27	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.
Genome Diagnostics Laboratory,University Medical Center Utrecht	RCV000494989	SCV000743298	likely benign	Breast-ovarian cancer, familial 2	2016-11-08	criteria provided, single submitter	clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000494989	SCV000744456	likely benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Color	RCV000163657	SCV000911199	likely benign	Hereditary cancer-predisposing syndrome	2017-03-07	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000426463	SCV000918832	uncertain significance	not specified	2018-05-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4494T>A alters a non-conserved nucleotide resulting in a synonymous change. 3/5 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 2.4e-05 in 245234 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (2.4e-05 vs 0.00075), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4494T>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.