13-32319275-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_001406722.1(BRCA2):c.-104C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
BRCA2
NM_001406722.1 5_prime_UTR_premature_start_codon_gain
NM_001406722.1 5_prime_UTR_premature_start_codon_gain
Scores
3
13
Clinical Significance
Conservation
PhyloP100: 0.616
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.35278362).
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000530893 | c.-104C>T | 5_prime_UTR_premature_start_codon_gain_variant | 3/27 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000380152.8 | c.266C>T | p.Pro89Leu | missense_variant | 3/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893 | c.-104C>T | 5_prime_UTR_variant | 3/27 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.266C>T | non_coding_transcript_exon_variant | 2/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251308Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135852
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461508Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727070
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 11, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 494C>T; Observed in individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer; however, has also been reported in healthy controls, as well as in an affected individual harboring a pathogenic variant in BRCA1 (Muller et al., 2011; Abulkhair et al., 2018; Mathias et al., 2019; Abu-Helalah et al., 2020; You et al., 2020; Dong et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 32377563, 29884841, 31432501, 30199306, 30287823, 33067490, 32467295, 33471991, 34218100, 21939546, 32211327) - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 30, 2023 | a variant of uncertain significance in the BRCA2 gene (p.Pro89Leu). This sequence change replaces proline, which is neutral and non polar, with leucine, which is neutral and non-polar, at codon 89 of the BRCA2 protein (p.Pro89Leu). This variant is present in population databases (rs748609599, gnomAD 0.006%). This missense change has been observed in individual(s) with a personal or family history of breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 21939546, 30199306, 31432501, 33067490). ClinVar contains an entry for this variant (Variation ID: 409565). In silico analysis supports that this missense variant does not alter protein structure/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. Pathogenic variants in the BRCA2 gene are associated with hereditary breat/ovarian cancer syndrome. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2024 | The p.P89L variant (also known as c.266C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 266. The proline at codon 89 is replaced by leucine, an amino acid with similar properties. This alteration has been identified in 1/2,461 index cases of high-risk individuals screened for variants in BRCA1/2 and in individuals diagnosed with breast and/or pancreatic cancer (Muller D et al. BMC Med. Genet. 2011; 12:121; Abulkhair O et al. J Glob Oncol. 2018 Aug;4:1-9; Schwartz M et al. Clin Genet, 2019 12;96:579-584). This variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), and was detected in a cohort of 172 Chinese epithelial ovarian cancer patients (You Y et al. Front Oncol, 2020 Mar;10:295). This alteration has also been reported in 0/7,051 unselected breast cancer patients and 1/1,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 26, 2022 | This missense variant replaces proline with leucine at codon 89 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with breast cancer and a family affected with breast and/or ovarian cancer (PMID: 21939546, 30199306, 34218100). This variant also has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001292) and another breast cancer case-control study in 1/11241 unaffected individuals and absent in 7051 cases (PMID: 30287823). This variant has been reported in one individual each affected with pancreatic and prostate cancer (PMID: 31214711, 31432501). This variant has been identified in 4/251308 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2024 | Variant summary: BRCA2 c.266C>T (p.Pro89Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.266C>T has been reported in the literature in individuals with a personal- and/or family history of Hereditary Breast and Ovarian Cancer (examples: Muller_2011, Abulkhair_2018, Abu-Helalah_2021, Combrink_2021, Dorling_2021, Song_2024) and pancreatic adenocarcinoma (Schwartz_2019), however it was also found in unaffected controls (Momozawa_2018, Dorling_2021, Dong_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33067490, 30199306, 34218100, 32467295, 33471991, 30287823, 21939546, 31432501, 38298632, 32641407). ClinVar contains an entry for this variant (Variation ID: 409565). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 23, 2019 | - - |
BRCA2-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 23, 2022 | The BRCA2 c.266C>T variant is predicted to result in the amino acid substitution p.Pro89Leu. This variant has been reported in individuals with breast, ovarian, and/or pancreatic cancer (Table 6, Abulkhair et al. 2018. PubMed ID: 30199306; Table 2, Schwartz et al. 2019. PubMed ID: 31432501; Table S1, You et al. 2020. PubMed ID: 32211327; Table S1, Abu-Helalah et al. 2020. PubMed ID: 33067490). The vast majority of these studies interpreted this variant as uncertain significance. It has also been reported in healthy control individuals (Supplementary Data, Momozawa et al. 2018. PubMed ID: 30287823; Table S1, Dong et al. 2020. PubMed ID: 32467295). This variant is reported in 4 of ~251,000 of alleles in gnomAD (http://gnomad.broadinstitute.org/variant/13-32893412-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/409565/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2024 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 11, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the BRCA2 protein (p.Pro89Leu). This variant is present in population databases (rs748609599, gnomAD 0.006%). This missense change has been observed in individual(s) with a personal or family history of breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 21939546, 30199306, 31432501, 32211327, 33067490). ClinVar contains an entry for this variant (Variation ID: 409565). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of disorder (P = 0.0547);Loss of disorder (P = 0.0547);
MVP
MPC
0.061
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at