rs41293479
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000059.4(BRCA2):c.3326C>T(p.Ala1109Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000476 in 1,597,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1109P) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3326C>T | p.Ala1109Val | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3326C>T | p.Ala1109Val | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000339 AC: 8AN: 236298Hom.: 0 AF XY: 0.0000391 AC XY: 5AN XY: 127872
GnomAD4 exome AF: 0.0000512 AC: 74AN: 1445594Hom.: 0 Cov.: 33 AF XY: 0.0000376 AC XY: 27AN XY: 717452
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 31, 2023 | In the published literature, this variant has been reported in individuals with breast cancer (PMID: 25452441 (2015), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), and head and neck squamous cell carcinomas (HNSCC) (PMID: 28678401 (2017)). This variant is also reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). A functional assay found this variant had a mild effect on the ability of BRCA2 to restore homologous recombination in BRCA2-deficient cells (PMIDs: 22293751 (2012)). The frequency of this variant in the general population, 0.000056 (7/124418 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 damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . However, an in vitro functional assay showed this variant had no effect on splicing (PMID: 29280214 (2018)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3554C>T; This variant is associated with the following publications: (PMID: 28678401, 25452441, 22293751, 26689913, 22476429, 29280214, 24817641, 28726806, 32377563, 29884841, 31131967, 31112341, 31294896, 33471991) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 05, 2020 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2019 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 10, 2022 | - - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 27, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2021 | 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 (gnomAD). 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 with a personal and/or family history of breast- and/or ovarian cancer (Lu_2012, Couch_2015, Dorling_2021), and with other tumor phenotypes (Chandrasekharappa_2017), but was also found in healthy controls (Dorling_2021 through LOVD). These reports do 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 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). In addition, a recent multifactorial likelihood analysis predicted this variant to be likely benign (Parsons_2019). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (likely benign (n=3), VUS (n=4)), some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at