Submissions for variant NM_000059.3(BRCA2):c.9433G>C (p.Val3145Leu) (rs587776476)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129373	SCV000184137	likely benign	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing	Other data supporting benign classification;In silico models in agreement (benign)
Invitae	RCV001088631	SCV000283368	likely benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000499802	SCV000592287	uncertain significance	not specified	2014-01-24	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000590711	SCV000695239	uncertain significance	not provided	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9433G>C (p.Val3145Leu) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. Val3145 is not conserved across species and located in the Nucleic acid-binding, OB-fold domain (Interpro); a Leu residue can be found at this position in zebrafish, suggesting that this missense change is tolerate.This variant was found in 1/121308 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign without providing evidence to independently evaluate. Furthermore, this variant was found to co-occur with a pathogenic BRIP1 variant (c.2392C>T; p.R798*) in one LCA internal specimen; however the occurrence of one pathogenic BRIP1 variant may not explain a cancer phenotype, as the pathogenicity of this specific LOF variant in BRIP1 (p.Arg798Ter) in addition to all other truncating variants in regards to their breast cancer risk have recently been called into question (PMID:26921362). Taken together, this variant is classified as VUS until additional information is available.
GeneDx	RCV000499802	SCV000715915	likely benign	not specified	2017-04-13	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.
Color	RCV000129373	SCV000903031	benign	Hereditary cancer-predisposing syndrome	2016-11-18	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000144220	SCV001267534	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001114170	SCV001272016	uncertain significance	Fanconi anemia, complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP)	RCV000144220	SCV000189323	benign	Breast-ovarian cancer, familial 2	2012-01-04	no assertion criteria provided	clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital	RCV000761164	SCV000891080	uncertain significance	Anaplastic/large cell medulloblastoma	2017-04-03	no assertion criteria provided	clinical testing