chr11-108279501-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):c.3295G>A(p.Asp1099Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,609,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3295G>A | p.Asp1099Asn | missense_variant | Exon 23 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000286 AC: 7AN: 244464Hom.: 0 AF XY: 0.0000378 AC XY: 5AN XY: 132216
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1457008Hom.: 0 Cov.: 30 AF XY: 0.0000290 AC XY: 21AN XY: 724648
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3
The c.3295G>A (p.Asp1099Asn) sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419) . ClinVar contains an entry for this variant (Variation ID: 188196).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. -
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The observed missense variant c.3295G>A(p.Asp1099Asn) in ATM gene has been reported previously in multiple individuals with various cancers (Yurgelun MB, et al., 2017, Howitt BE, et al., 2015). This variant is reported with 0.003% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Beningn/ Uncertain Significance (multiple submissions).The amino acid Asp at position 1099 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Asp1099Asn in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Uncertain Significance. -
Ataxia-telangiectasia syndrome Uncertain:2
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1099 of the ATM protein (p.Asp1099Asn). This variant is present in population databases (rs372966951, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682, 21787400, 28135145, 30093976). ClinVar contains an entry for this variant (Variation ID: 188196). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM 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. -
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Hereditary cancer-predisposing syndrome Benign:2
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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 Uncertain:1
Variant summary: ATM c.3295G>A (p.Asp1099Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3295G>A has been reported in the literature in individuals affected with Breast Cancer, Lymphoma, Mullerian Adenocarcinoma, Colorectal cancer and Pediatric cancer predisposition syndrome without evidence for causality (example, Fang_2003, Tavtigian_2009, Goldgar_2011, Howitt_2015, Yurgelun_2017, Tung_2016, Young_2015, Chan_Oncotarget_2018, Chan_Genomic Med_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has classified the variant as likely benign and four others have classified it as variant of unknown significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
ATM-related disorder Uncertain:1
The ATM c.3295G>A variant is predicted to result in the amino acid substitution p.Asp1099Asn. This variant has been reported in patients with breast or colorectal cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S2, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD and is listed in ClinVar with conflicting interpretation of likely benign (1) and uncertain (7) (https://www.ncbi.nlm.nih.gov/clinvar/variation/188196/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, and other cancers (PMID: 19781682, 28135145, 30455982, 30093976); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976, 26976419) -
Malignant tumor of breast Uncertain:1
The ATM p.Asp1099Asn variant was identified in 4 of 15480 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and colorectal cancer and was not identified in 7694 control chromosomes from healthy individuals (Tavtigian 2009, Goldgar 2011, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs372966951) as "With Uncertain significance allele", and in ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Integrated Genetics). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 7 of 239322 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5374 chromosomes (freq: 0.0002), and South Asian in 6 of 30298 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Asp1099 residue is not conserved in mammals and 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at