11-108325341-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000051.4(ATM):c.6604T>G(p.Tyr2202Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,610,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6604T>G | p.Tyr2202Asp | missense_variant | Exon 46 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000266 AC: 4AN: 150444Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251042Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135710
GnomAD4 exome AF: 0.0000562 AC: 82AN: 1460204Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 726444
GnomAD4 genome AF: 0.0000266 AC: 4AN: 150444Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1AN XY: 73388
ClinVar
Submissions by phenotype
not specified Uncertain:3
- -
- -
Variant summary: ATM c.6604T>G (p.Tyr2202Asp) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121096 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (1.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.6604T>G, has been reported in the literature in individuals affected with chronic lymphocytic leukemia and head and neck squamous cell carcinoma (Mansouri 2014, Lu 2015), however it also was found in women, older than age 70 years who have never had cancer (in the FLOSSIES database). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Ataxia-telangiectasia syndrome Uncertain:2
- -
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2202 of the ATM protein (p.Tyr2202Asp). This variant is present in population databases (rs730881311, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or head and neck squamous carcinoma (PMID: 26689913, 29522266). ClinVar contains an entry for this variant (Variation ID: 181882). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein 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. -
not provided Uncertain:2
The ATM p.Tyr2202Asp variant was identified by Mansouri (2013) in an individual with chronic myelogenous leukemia. The variant was also identified in dbSNP (ID: rs730881311) as “With Uncertain significance allele”, and in ClinVar (as uncertain significance by GeneDx, Ambry Genetics, Invitae, University of Chicago, and Color Genomics). The variant was not identified in the Cosmic, MutDB, LOVD 3.0, or ATM-LOVD database. The variant was identified in control databases in 3 of 245856 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15300 chromosomes (freq: 0.00007), European (Non-Finnish) in 2 of 111502 chromosomes (freq: 0.000018); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. 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 p.Tyr2202 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; 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. This variant is classified as a variant of uncertain significance. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and other cancers (PMID: 24172824, 26689913, 29522266); This variant is associated with the following publications: (PMID: 24172824, 27720647, 29522266, 26689913, 33436325, 23532176) -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces tyrosine with aspartic acid at codon 2202 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 29522266) and head and neck squamous cell carcinoma (PMID: 26689913). In a large international case-control study, this variant was reported in 5/60461 breast cancer cases and 8/53453 controls (OR=0.553, 95%CI 0.181 to 1.689, p-value=0.406; PMID: 33471991). This variant has been identified in 3/251042 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. -
The p.Y2202D variant (also known as c.6604T>G), located in coding exon 45 of the ATM gene, results from a T to G substitution at nucleotide position 6604. The tyrosine at codon 2202 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has been reported in 3/13087 breast cancer cases and 2/5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Familial cancer of breast Uncertain:1Benign:1
- -
This variant is considered likely benign. 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]. -
Breast and/or ovarian cancer Uncertain:1
- -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at