chr11-108248927-T-G
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP2_StrongBS1
This summary comes from the ClinGen Evidence Repository: The ATM c.1066-6T>G variant has a GnomAD (v2.1.1) filtering allele frequency of 0.2081% (NFE) which is above the ATM BS1 threshold of .05% (BS1). In silico predictors (SpliceAI Acceptor Loss 0.62; MaxEntScan -2.49) are indeterminate about whether this variant affects splicing. This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 26957, 500031). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel LINK:https://erepo.genome.network/evrepo/ui/classification/CA151456/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Benign. The variant received -8 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.1066-6T>G | splice_region intron | N/A | NP_000042.3 | |||
| ATM | NM_001351834.2 | c.1066-6T>G | splice_region intron | N/A | NP_001338763.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.1066-6T>G | splice_region intron | N/A | ENSP00000501606.1 | |||
| ATM | ENST00000452508.7 | TSL:1 | c.1066-6T>G | splice_region intron | N/A | ENSP00000388058.2 | |||
| ATM | ENST00000531525.3 | TSL:1 | c.1066-6T>G | splice_region intron | N/A | ENSP00000434327.3 |
Frequencies
GnomAD3 genomes 0.00137 AC: 208AN: 151992Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00134 AC: 320AN: 239436 AF XY: 0.00132 show subpopulations
GnomAD4 exome AF: 0.00217 AC: 3138AN: 1447396Hom.: 7 Cov.: 32 AF XY: 0.00213 AC XY: 1536AN XY: 720140 show subpopulations
Age Distribution
GnomAD4 genome 0.00137 AC: 208AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83AN XY: 74398 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:9
BS1, BP2_mod
This variant is associated with the following publications: (PMID: 26898890, 28779002, 28643015, 21933854, 10677309, 15101044, 11606401, 25040471, 27067391, 26250988, 18573109, 26662178, 27798748, 27296296, 19781682, 16958054, 27803004, 28627265, 28691344, 16914028, 28652578, 20544271, 30549301, 11830610, 32918381)
ATM: PP3, BS2
Ataxia-telangiectasia syndrome Uncertain:2Benign:3
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Hereditary cancer-predisposing syndrome Uncertain:2Benign:3
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.
not specified Benign:4
Variant summary: ATM c.1066-6T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Although the variant was reported to be associated with a partial splicing defect (see e.g. Broeks_2000, Dork_2001, Fang_2010), several patient samples were also reported to have second-site mutations that could also affect splicing, therefor the splicing effect of the variant in isolation is currently unclear (Tavtigian_2009, Fievet_2019). The variant allele was found at a frequency of 0.0014 in 270694 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.0024 in the gnomAD database (including 2 homozygotes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, the variant was reported to be found in the FLOSSIES database in 33/7325 European American women, who were older than age 70 years and have never had cancer. The allele frequency in this cohort is also higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0023 vs. 0.001), further supporting a benign role for the variant. Though the variant has been reported in the literature in homozygous individuals affected with Ataxia Telangiectasia (A-T), these patients carried second-site mutations that were sufficient to explain the A-T phenotype (Tavtigian_2009, Fievet_2019). The variant was also reported in compound heterozygosity, with (potential) pathogenic ATM variants in trans, in an individual affected with breast cancer (Fang_2010) and also in a patient with multiple myeloma and (per authors) an atypical, milder A-T phenotype (Austen_2008). Therefore these reports do not support the association of the variant with A-T. The variant, c.1066-6T>G, also has been reported in the literature in individuals affected with Breast Cancer, however in most of the cases co-occurrence and/or co-segregation data was not provided, therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Moreover, in case-control studies the variant did not have significantly increased risk association with breast cancer (Dork_2001, Bernstein_2006, Ding_2011). One recent case-control study reported the variant with an increased risk for CLL (OR: 3.29), however this analysis had a relatively small sample size and most patients were sporadic cases, thus this risk association might not be reliable (Tiao 2017). Twelve other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as VUS (4x), likely benign (3x) / benign (5x). Based on the evidence outlined above, the variant was classified as benign.
Familial cancer of breast Uncertain:1Benign:1
This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Intellectual disability Uncertain:1
Breast and/or ovarian cancer Benign:1
ATM-related cancer predisposition Benign:1
The ATM c.1066-6T>G variant has a GnomAD (v2.1.1) filtering allele frequency of 0.2081% (NFE) which is above the ATM BS1 threshold of .05% (BS1). In silico predictors (SpliceAI Acceptor Loss 0.62; MaxEntScan -2.49) are indeterminate about whether this variant affects splicing. This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 26957, 500031). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Benign:1
Malignant tumor of breast Benign:1
The ATM c.1066-6T>G variant was identified in 51 of 18,694 proband chromosomes (frequency: 0.003) from individuals or families with chronic lymphocatic leukemia, breast or ovarian cancer and was present in 70 of 27,754 control chromosomes (frequency: 0.003) from healthy individuals (Ding 2010, Tiao 2017). The variant was identified in dbSNP (rs201686625) as “with other allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Integrated Genetics and 5 other submitters; as benign by Invitae, Color, Athena Diagnostics and 2 other submitters; and as likely benign by GeneDx and 2 other submitters) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 357 of 266,346 chromosomes (2 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23,658 chromosomes (freq: 0.0003), Other in 2 of 6198 chromosomes (freq: 0.0003), Latino in 19 of 32,652 chromosomes (freq: 0.0006), European in 286 of 123,010 chromosomes (freq: 0.002), Finnish in 18 of 25,254 chromosomes (freq: 0.0007), and South Asian in 25 of 27,738 chromosomes (freq: 0.0009); it was not observed in the Ashkenazi Jewish or East Asian populations. The variant was identified by our laboratory in multiple patients with pathogenic variants in BRCA2 (including c.1929del, p.Arg645Glufs*15 and c.755_758del, p.Asp252Valfs*24). The variant was also identified in the homozygous state in a patient with ataxia telangiectasia (Dork 2001), for whom alternate pathogenic variants were subsequently identified (Tavtigian 2009). A patient with mild ataxia telangiectasia was found to carry this variant in the compound heterozygous state and had reduced ATM protein expression and kinase activity, indicating this variant does not fully abolish protein expression and function (Austen 2016). Additionally, this variant leads to an increase in exon 11 skipping, although some exon 11 skipping is found in controls who do not carry this variant (Soukupova 2007). The c.1066-6T>G variant is located in the 3' splice region and does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence; variants involving these positions sometimes affect splicing and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at