rs81002867
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_000059.4(BRCA2):c.9501+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,776 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 Benign (★★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000069 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 intron
NM_000059.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.32
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 Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 13-32394942-A-C is Benign according to our data. Variant chr13-32394942-A-C is described in ClinVar as [Benign]. Clinvar id is 38243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394942-A-C is described in Lovd as [Benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9501+9A>C | intron_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9501+9A>C | intron_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250924Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135676
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GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461550Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54AN XY: 727066
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | literature only | Counsyl | Jul 31, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000013 - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 06, 2008 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 14, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 22, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 22, 2015 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, no assertion criteria provided | research | Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology | Mar 01, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Fanconi anemia complementation group D1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 19, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 07, 2016 | Variant Summary: The c.9501+9A>C variant is a BRCA2 intronic variant located at a position not widely known to affect splicing. 4/5 splicing prediction programs (via Alamut) suggest no significant effect on splicing, ESE finder predicts no change to binding motifs, and Mutation Taster predicts the variant to be a polymorphism. The observed allele frequency in controls including the large and diverse ExAC cohort is 4/121488(1/30372), which does not exceed the maximal expected alelle frequency for a pathogenic BRCA2 variant (1/1333). However, it has been reported to co-occur with several potentially pathogenic variant in BRCA2 (c.5909C>A, p.Ser1970X - UMD; BRCA2 c.5410_5411delGT (p.Val1804Lysfs) - BIC; BRCA2 c.9382C>T (p.Arg3128Ter) - BIC and BRCA1 IVS3+3A>C (Claes_2003). In addition, multiple reputable databases/clinical diagnostic labs (UMD, GeneDx, and SCRP) and publications (Lindor_2012 and Easton_2007) classify the variant as benign/neutral. Furthermore, functional studies from multiple independent publications report that the variant of interest does not affect splicing (Campos_2003, Claes_2003, Houdayer_2012, and Whiley_2011). Taken together, this BRCA2 intronic variant has been classified as Benign. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 c.9501+9A>C variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian (Diez 2003) and was not identified in 200 control chromosomes from healthy individuals (Claes 2003). The variant was also identified in dbSNP (ID: rs81002867) as With other allele, ClinVar (classified as benign by GeneDx, ARUP, Color Genomics, Laboratory Corporation of America, Invitae, SCRP; as likely benign by Counsyl), Clinvitae, COGR (likely benign/benign), LOVD 3.0, UMD-LSDB (36X uncertain significance), BIC Database (unknown clinical importance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.5909C>A (p.Ser1970X), increasing the likelihood that the c.9501+9A>C variant does not have clinical significance. The variant was not identified in ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 17 of 276704 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6454 chromosomes (freq: 0.0002), Latino in 3 of 34398 chromosomes (freq: 0.0001), European in 13 of 126364 chromosomes (freq: 0.0001); but not in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, mRNA and bioinformatics analysis of the variant showed no alteration effect at the cDNA and protein level (Easton 2007, Campos 2003, Claes 2003, Houdayer 2012, Lindor 2012, Whiley 2011, Thery 2011). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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