13-32325111-C-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001406722.1(BRCA2):c.-18C>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 0.0000149 in 1,607,402 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 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
2
14
Clinical Significance
Conservation
PhyloP100: -0.773
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.047331303).
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000530893 | c.-18C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 4 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000380152.8 | c.352C>T | p.Arg118Cys | missense_variant | Exon 4 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893 | c.-18C>T | 5_prime_UTR_variant | Exon 4 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.352C>T | non_coding_transcript_exon_variant | Exon 3 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152128Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
10
AN:
152128
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251000Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135718
GnomAD3 exomes
AF:
AC:
10
AN:
251000
Hom.:
AF XY:
AC XY:
2
AN XY:
135718
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000962 AC: 14AN: 1455156Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7AN XY: 724336
GnomAD4 exome
AF:
AC:
14
AN:
1455156
Hom.:
Cov.:
30
AF XY:
AC XY:
7
AN XY:
724336
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74434
GnomAD4 genome
AF:
AC:
10
AN:
152246
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
74434
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
0
ExAC
AF:
AC:
7
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 13, 2020 | DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.352C>T, in exon 4 that results in an amino acid change, p.Arg118Cys. This sequence change has been previously described in a patient with breast cancer but no additional information was provided (PMID: 27257965). This sequence change has been described in the gnomAD database with a low population frequency of 0.025% in the African subpopulation (dbSNP rs375125172). The p.Arg118Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Arg118Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg118Cys change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2024 | Variant summary: BRCA2 c.352C>T (p.Arg118Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing, although a disruption of an ESE splice site is predicted. In a minigene assay system, this variant was reported to produce 74% of the canonical transcript and low levels of delta 4, delta 4,5 and delta 4,5,6 transcripts (Fraile-Bethencourt_2019). However, the in-vivo impact of these findings have yet to be corroborated by functional studies. The variant allele was found at a frequency of 4e-05 in 251000 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.352C>T has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (e.g. Zhang_2016, Bhaskaran_2019). A co-occurrence with another pathogenic variant has also been reported (BRCA1 c. 3700_3704del, p. Val1234Glnfs*8; Zografos_2022), providing supporting evidence for a benign role. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. ClinVar contains an entry for this variant (Variation ID: 91803). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2018 | The BRCA2 c.352C>T; p.Arg118Cys variant (rs375125172), is reported in the literature in at least one individual affected with breast cancer (Zhong 2016). This variant is reported with conflicting classifications in ClinVar (Variation ID: 91803), and is found in the African population with an overall allele frequency of 0.03% (4/15,298 alleles) in the Genome Aggregation Database. The arginine at codon 118 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg118Cys variant is uncertain at this time. References: Zhong X et al. Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients. PLoS One. 2016 Jun 3;11(6):e0156789. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, some of whom had additional variants that may explain their phenotype (Zhong et al., 2016; Andrikopoulou et al., 2022; Zografos et al., 2022); Published functional studies demonstrate aberrant splicing in a minority of transcripts (Fraile-Bethencourt et al., 2019); Also known as 580C>T; This variant is associated with the following publications: (PMID: 27257965, 31131967, 30702160, 25846551, 11948123, 35127508, 36011273, 30287823, 33471991, 34313030, 31825140, 30883759) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 14, 2023 | The frequency of this variant in the general population, 0.00025 (4/16246 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 27257965 (2016), 30702160 (2019), 36011273 (2022)) and unaffected individuals (PMID: 30287823 (2018), 33471991 (2021)). This variant was found to impact splicing in one study (PMID: 30883759 (2019)) but published functional studies describing its effect on protein function have not been found. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Arg118Cys variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, MutDB, BIC, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs375125172) as With Uncertain significance allele, ClinVar (classified as likely benign by Ambry Genetics; classified as uncertain significance by GeneDx, Invitae, SCRP), Cosmic (classified as Neutral (score 0.00)), LOVD 3.0, and UMD-LSDB (4X classified as unclassified variant). The variant was identified in control databases in 9 of 245844 chromosomes at a frequency of 0.000037 (Genome Aggregation Consortium Feb 27, 2017). The p.Arg118 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domain, the clinical significance of which is uncertain. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 08, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 03, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 06, 2006 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Jan 22, 2020 | This variant has been reported in the literature in individuals with breast cancer (Zhong 2016, Bhaskaran 2019). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2025 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
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
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Vest4
MVP
MPC
0.022
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at