Submissions for variant NM_000059.4(BRCA2):c.9086C>T (p.Ala3029Val)

gnomAD frequency: 0.00003  dbSNP: rs80359162

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045708	SCV000073721	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3029 of the BRCA2 protein (p.Ala3029Val). This variant is present in population databases (rs80359162, gnomAD 0.02%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 31102422). ClinVar contains an entry for this variant (Variation ID: 52744). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000129861	SCV000184678	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657008	SCV000296524	likely benign	not provided	2022-11-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000077459	SCV000488156	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000657008	SCV000566257	uncertain significance	not provided	2018-11-27	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9086C>T at the cDNA level, p.Ala3029Val (A3029V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 9314C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Ala3029Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala3029Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000479673	SCV000916966	uncertain significance	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9086C>T (p.Ala3029Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249594 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9086C>T has been reported in the literature without strong evidence for or against pathogenicity (Karchin_2008, de Smith_2016). In a cell-based homology directed DNA repair activity assay, this variant was found to have neutral effect (Hart_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly benign.
Mendelics	RCV000077459	SCV001139246	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129861	SCV001353223	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 3029 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29884841, 35736817). This variant has been reported in an individual affected with breast cancer and another individual affected with leukemia (PMID: 31102422, 33471991; Leiden Open Variation Database DB-ID BRCA2_000401).This variant has been identified in 8/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077459	SCV004101684	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3029 of the BRCA2 protein (p.Ala3029Val). This variant is present in population databases (rs80359162, gnomAD 0.02%). This variant has been reported in an individual affected with breast cancer and another individual affected with leukemia (PMID: 31102422, 33471991; Leiden Open Variation Database DB-ID BRCA2_000401). Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. (Variation ID: 52744) . A functional study has reported that this variant does not impact BRCA1 function in a homology-directed repair assay (PMID: 29884841).in-silico tools predict a damaging effect of the variant on protein function.. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003398621	SCV004103481	uncertain significance	BRCA2-related condition	2023-06-06	criteria provided, single submitter	clinical testing	The BRCA2 c.9086C>T variant is predicted to result in the amino acid substitution p.Ala3029Val. This variant has been reported in an individual with acute lymphoblastic leukemia (Table S1, de Smith et al. 2019. PubMed ID: 31102422). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954019-C-T). IT is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52744/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492370	SCV004240373	likely benign	Breast and/or ovarian cancer	2022-12-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077459	SCV004846119	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 3029 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29884841, 35736817). This variant has been reported in an individual affected with breast cancer and another individual affected with leukemia (PMID: 31102422, 33471991; Leiden Open Variation Database DB-ID BRCA2_000401).This variant has been identified in 8/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077459	SCV000109257	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-11-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077459	SCV000147532	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing