rs576884305
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.3601T>A(p.Phe1201Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,416 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 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ATM | NM_000051.4 | c.3601T>A | p.Phe1201Ile | missense_variant | Exon 25 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250942Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135636
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1461136Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726840
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74454
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with early-onset breast cancer and acute myeloid leukemia (Lu et al., 2015; Maxwell et al., 2015); This variant is associated with the following publications: (PMID: 19781682, 26689913, 25503501) -
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Hereditary cancer-predisposing syndrome Uncertain:2
The p.F1201I variant (also known as c.3601T>A), located in coding exon 24 of the ATM gene, results from a T to A substitution at nucleotide position 3601. The phenylalanine at codon 1201 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in 1/278 individuals from a cohort of BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43) and was identified as germline in a cohort of 690 patients with myeloid malignancy (Li ST et al. Leukemia, 2020 Jun;34:1675-1678). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This missense variant replaces phenylalanine with isoleucine at codon 1201 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and prostate cancer in the literature (PMID: 25503501, 32832836). This variant has been identified in 7/282334 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. -
Ataxia-telangiectasia syndrome Uncertain:1Benign: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.3601T>A variant is predicted to result in the amino acid substitution p.Phe1201Ile. This variant has been reported in breast cancer and myeloid leukemia cohorts (Supplementary Table 1 in Maxwell et al. 2014. PubMed ID: 25503501; Supplementary Table 5 in Li et al. 2020. PubMed ID: 31911633). It was also documented in an individual from a prostate cancer study; however, affected status was not specified (Supplemental Table 2 in Matejcic et al. 2020. PubMed ID: 32832836). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/220809/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at