chr11-108365152-C-T
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_000051.4(ATM):c.8921C>T(p.Pro2974Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000979 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2974T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.8921C>T | p.Pro2974Leu | missense_variant | Exon 62 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152120Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000756 AC: 19AN: 251398 AF XY: 0.000110 show subpopulations
GnomAD4 exome AF: 0.000101 AC: 148AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69AN XY: 727238 show subpopulations
GnomAD4 genome 0.0000657 AC: 10AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74426 show subpopulations
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:4Benign:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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not provided Uncertain:4
ATM: PS3:Supporting, BP4 -
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Observed in individuals with breast, ovarian, colorectal, biliary, or pancreatic cancer, but also in unaffected controls (PMID: 24326041, 28726808, 29522266, 32091409, 33309985, 34326862, 36243179); Published functional studies demonstrate mRNA expression levels equivalent to wild type, lower repair efficiency after DNA damage, partial loss of homologous recombination repair activity, and reduction in phosphorylation activity (PMID: 12511424, 31160347); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24326041, 23636326, 28652578, 32566746, 32601921, 33309985, 14628072, 12969974, 12511424, 28873162, 26991699, 23555315, 1806608, 16941484, 29522266, 31160347, 30287823, 26689913, 20232390, 34426522, 11185744, 10923033, 15696190, 32980694, 32091409, 28726808, 33471991, 34326862, 36243179, 23532176) -
BP4 -
Hereditary cancer-predisposing syndrome Benign:3
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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:2
Variant summary: ATM c.8921C>T (p.Pro2974Leu) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 1632190 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0044 (in the jMorp database). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.3 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 East Asian origin. In addition, this variant has also been reported in 2/2559 African American women who were older than age 70 and cancer free (in the FLOSSIES database). c.8921C>T has been reported in the literature in individuals affected with Breast Cancer (BrC) and other tumor phenotypes. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. Two recent case-control association studies involving breast cancer patients and controls of Japanese ancestry found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of this study classified the variant as benign (Momozawa_2018, Fujita_2020). However, another recent case-control association study, involving breast cancer patients and controls of Chinese ancestry (Guo_2019), found an enrichment of this variant in cases, suggesting this variant could be associated with a risk for late onset BrC, though no statistically significant enrichment of this variant was observed in early-onset BrC patients (<45 years old). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect suggest a partial loss of ATM activity and a dominant-negative effect of the repair ability of this p.Pro2974Leu variant in ATM has been proposed (Oguchi_2003, Guo_2019). Due to a lack of complete loss of activity, the correlation of these findings to the in-vivo mechanism of disease remains unclear. The following publications have been ascertained in the context of this evaluation (PMID: 33309985, 32601921, 31160347, 23555315, 24326041, 15696190, 26689913, 30287823, 12511424, 20232390, 12969974, 28652578). ClinVar contains an entry for this variant (Variation ID: 135787). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Breast and/or ovarian cancer Uncertain:1
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.8921C>T variant is predicted to result in the amino acid substitution p.Pro2974Leu. This variant has been reported in a child with acute lymphoblastic leukemia and functional studies indicated a possible dominant negative effect (Oguchi et al. 2003. PubMed ID: 12511424). In particular, this variant impacts the ability of the ATM protein to phosphorylate the p53 protein (Figure 3, Oguchi et al. 2003. PubMed ID: 12511424). The c.8921C>T variant has also been reported in individuals with breast cancer (Table S8, Harismendy et al. 2013. PubMed ID: 24326041; Gervas et al. 2020. PubMed ID: 32601921; Supp. Table 2, Chen et al. 2020. PubMed ID: 32091409). This variant was reported in 8 of 4,580 breast cancer cases and none of the 6,695 controls (Guo et al. 2019. PubMed ID: 31160347); however, in a different study this variant was found at similar frequencies in breast cancer cases and controls and was interpreted as benign (Momozawa et al. 2018. PubMed ID: 30287823). Functional analysis by Guo et al. utilized a well established GFP-reporter system and found that homologous recombination and DNA repair were significantly reduced with the p.Pro2974Leu variant and also supported a possible dominant negative effect (Guo et al. 2019. PubMed ID: 31160347). The c.8921C>T variant was also reported in a cohort of colorectal cancer patients and interpreted as benign based on similar frequencies of the variant between cases and controls (Supp. Table S5, Fujita et al. 2020. PubMed ID: 33309985). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135787/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Malignant tumor of breast Uncertain:1
The ATM p.Pro2974Leu variant was identified in 1 of 14 proband chromosomes (frequency: 0.07) from individuals or families with acute lymphoid and myeloid leukemia with mixed lineage leukemia (MLL) (Oguchi 2003). The variant was also identified in dbSNP (ID: rs139379666) as “With Uncertain significance allele”, in the ClinVar database as uncertain significance by Invitae, GeneDx, and Ambry Genetics. The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. In addition, the variant was identified in control databases in 23 of 277148 chromosomes at a frequency of 0.00008 (Genome Aggregation Consortium Feb 27, 2017); in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 1 of 4402 African American alleles (frequency: 0.0002). In one functional study, the p.Pro2974Leu variant in the PI-3 kinase domain of the ATM gene was identified in one patient with myeloid leukemia with a normal level expression of the ATM protein. The variant leads to a change in the secondary structure of the ATM protein, namely, loss of random coil between alpha helices. In vitro kinase studies showed that 8921T was defective in mediating p53-Ser15 phosphorylation. Thus, this change in the secondary structure of the PI-3 kinase domain may disrupt its enzymatic function. Expression of 8921T ATM in AT fibroblasts sowed only partial rescue of the radiosensitive phenotype. In addition, its expression in U2OS cells showed an interfering effect with the normal function of ATM. This finding strongly suggests pathogenicity. Furthermore, segregation analysis revealed the father of the affected child to be heterozygous for the variant, thus excluding the possibility that the variant arising de novo in the patient. As of the writing of this study, the father remains disease free indicating a low penetrance. However, environmental factors such as exposure to top II inhibitors during development played a role in the development of MLL leukemia in this patient. The p.Pro2974 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 Phosphatidylinositol 3-/4-kinase, catalytic domain Armadillo-type fold functional domain(s) increasing the likelihood that it may have clinical significance. 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 breast ovarian cancer syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at