ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203645 SCV000072191 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1109 of the BRCA2 protein (p.Ala1109Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs41293479, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 25452441) and individuals affected with head and neck squamous cell carcinoma (PMID: 28678401). This variant has also been reported in the Breast Cancer Information Core database (PMID: 10923033). However, in one these individuals a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.3326C>T substitution in BRCA2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 51450). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In addition, an experimental study has shown that this missense change impairs BRCA2-APRIN interaction, however, the clinical significance of these findings are unclear (PMID: 22293751). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000129186 SCV000183922 likely benign Hereditary cancer-predisposing syndrome 2019-01-09 criteria provided, single submitter clinical testing Other data supporting benign classification;Co-occurence with mutation in same gene (phase unknown)
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
Integrated Genetics/Laboratory Corporation of America RCV000044178 SCV000694690 uncertain significance not specified 2019-09-07 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. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.2241delC, p.Asp749fsX4), 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). 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 (uncertain significance, n=4; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics,PreventionGenetics RCV000586235 SCV000805691 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing
Color RCV000129186 SCV000910877 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
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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