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	In silico models in agreement (benign);Other data supporting benign classification
Invitae	RCV001088631	SCV000283368	likely benign	Hereditary breast and ovarian cancer syndrome	2020-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499802	SCV000695239	likely benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9433G>C (p.Val3145Leu) results in a conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9433G>C has been reported in the literature in at-least one individual affected with cancer (example, McVeigh_2013). Theis report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( BRCA2 c.3847_3848delGT , p.V1283fs*2), providing supporting evidence for a benign role. Additionally, this variant was found to co-occur with a pathogenic BRIP1 variant (c.2392C>T; p.R798*) at our laboratory, however, this evidence is captured with caution as the pathogenicity of this specific loss of function (LOF) variant in BRIP1 (p.Arg798Ter) in addition to all other truncating BRIP1 variants in regards to their breast cancer risk has recently been called into question (PMID:26921362). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4). Based on the evidence outlined above and to reflect the emerging majority consensus in the field, the variant was re-classified as likely benign.
GeneDx	RCV001353675	SCV000715915	likely benign	not provided	2019-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23884708)
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital	RCV000761164	SCV000891080	uncertain significance	Anaplastic/large cell medulloblastoma	2017-04-03	criteria provided, single submitter	clinical testing
Color Health, Inc	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
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353675	SCV000592287	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Val3145Leu variant was not identified in the literature, nor was it identified in the dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project, HGMD, LOVD, COSMIC, UMD or BIC databases. The p.Val3145 residue is not conserved in mammals and the variant amino acid leucine (Leu) is present in zebrafish, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.