ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3326C>T (p.Ala1109Val) (rs41293479)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203645 SCV000072191 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129186 SCV000183922 likely benign Hereditary cancer-predisposing syndrome 2019-01-09 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
GeneDx RCV000586235 SCV000210313 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3326C>T at the cDNA level, p.Ala1109Val (A1109V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant, also defined as BRCA2 3554C>T using alternate nomenclature, has been observed in individuals with breast cancer, renal cancer, or head and neck squamous cell carcinoma, as well as in one individual from a high-risk breast and/or ovarian cancer family (Lu 2012, Couch 2015, Lu 2015, Chandrasekharappa 2017). Functional studies by Brough et al. (2012) found this variant impaired interaction between BRCA2 and APRIN and could not fully rescue homology-directed repair activity in BRCA2-deficient cells. BRCA2 Ala1109Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ala1109Val is located in the RAD51 binding domain (Roy 2012). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, splicing models predict that this variant may create a cryptic splice donor site and lead to abnormal splicing, however an RT-PCR assay showed no effect on splicing (Baert 2017). Based on currently available evidence, it is unclear whether BRCA2 Ala1109Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586235 SCV000600547 uncertain significance not provided 2019-06-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044178 SCV000694690 likely benign not specified 2020-11-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3326C>T (p.Ala1109Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 236298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3326C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lu_2012, Couch_2015) and head and neck cancer (Chandrasekharappa_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.2241del, p.Asp749fs), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Brough_2012). A different study reported the variant to have no effect on splicing (Baert_2018). Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). 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 (likely benign, n=3, VUS, n=3) some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000586235 SCV000805691 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129186 SCV000910877 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287670 SCV001474381 uncertain significance none provided 2020-07-05 criteria provided, single submitter clinical testing The BRCA2 c.3326C>T; p.Ala1109Val variant (rs41293479) is reported in the literature in several individuals with a personal or family history of breast/ovarian cancer or head/neck cancer, though it was not demonstrated to be disease-causing in these individuals (Chandrasekharappa 2017, Couch 2015, Lu 2012). This variant is found on nine chromosomes (9/267698 alleles) in the Genome Aggregation Database. The alanine at codon 1109 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, although a multifactorial likelihood analysis suggested this variant has a low probability of being disease-causing (Parsons 2019). Still, functional studies of this variant indicated slightly reduced interaction with a binding partner and moderately reduced activity in an assay of homology-directed repair (Brough 2012). In addition, computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a cryptic donor splice site, although RNA studies in one patient suggested no effect on splicing (Baert 2018). Due to limited and conflicting information, the clinical significance of the p.Ala1109Val variant is uncertain at this time. References: Baert A et al. Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11. Hum Mutat. 2018;39(4):515-526. Brough R et al. APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer. EMBO J. 2012;31(5):1160-1176. Chandrasekharappa SC et al. Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50. Cancer. 2017;123(20):3943-3954. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304-311. Lu W et al. Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer. 2012;11(3):381-385. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557-1578.
Sharing Clinical Reports Project (SCRP) RCV000077301 SCV000109098 likely benign Breast-ovarian cancer, familial 2 2012-11-27 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077301 SCV000146215 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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