Submissions for variant NM_007294.3(BRCA1):c.420T>C (p.Ser140=) (rs730881448)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495624	SCV000578265	likely benign	Breast-ovarian cancer, familial 1	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/).
GeneDx	RCV000159860	SCV000209907	benign	not specified	2014-09-15	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.
Invitae	RCV000464663	SCV000560250	likely benign	Hereditary breast and ovarian cancer syndrome	2017-12-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000159860	SCV000593664	likely benign	not specified	2016-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568214	SCV000665422	likely benign	Hereditary cancer-predisposing syndrome	2017-04-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign,In silico models in agreement (benign)
Color	RCV000568214	SCV000683162	likely benign	Hereditary cancer-predisposing syndrome	2017-06-06	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000589069	SCV000699120	uncertain significance	not provided	2017-04-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.420T>C (p.Ser140Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121398 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). One clinical diagnostic laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.