Submissions for variant NM_000059.4(BRCA2):c.9433G>C (p.Val3145Leu)

gnomAD frequency: 0.00001  dbSNP: rs587776476

Total submissions: 12

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	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	RCV001088631	SCV000283368	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	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 Molecular Pathology, St. Jude Children's Research Hospital	RCV001088631	SCV000891080	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129373	SCV000903031	benign	Hereditary cancer-predisposing syndrome	2016-11-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000144220	SCV001267534	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001353675	SCV004220653	uncertain significance	not provided	2023-07-17	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 23884708 (2014) and 34326862 (2021)). The frequency of this variant in the general population, 0.000026 (3/113678 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000144220	SCV000189323	benign	Breast-ovarian cancer, familial, susceptibility to, 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.
PreventionGenetics, part of Exact Sciences	RCV004532550	SCV004730014	uncertain significance	BRCA2-related disorder	2023-10-25	no assertion criteria provided	clinical testing	The BRCA2 c.9433G>C variant is predicted to result in the amino acid substitution p.Val3145Leu. This variant has been reported in one individual with a personal and family history of breast cancer (Table S4, Bhai et al 2021. PubMed ID: 34326862). It was also reported in one individual in an Irish cohort with suspected hereditary breast and ovarian cancers; however, specific information related to this patient's phenotype and cancer history was not provided (McVeigh et al. 2014. PubMed ID: 23884708). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32969002-G-C) and has conflicting interpretations in ClinVar ranging from uncertain significance to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/141038/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.