11-108345804-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000051.4(ATM):c.8480T>G(p.Phe2827Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,578 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8480T>G | p.Phe2827Cys | missense_variant | Exon 58 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461578Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727090
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATM function (PMID: 9000145, 19431188, 25040471). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3022). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 8755918, 30549301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2827 of the ATM protein (p.Phe2827Cys). -
Variant summary: ATM c.8480T>G (p.Phe2827Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. c.8480T>G has been reported in the literature in at least one individual affected with Ataxia-Telangiectasia and cited by several others (McConville_1996 cited in Jackson_2016, Schon_2019, Thompson_2005, Stankovic_1998). Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced stability (example, Barone_2009, Taylor_2015). The following publications have been ascertained in the context of this evaluation (PMID: 35710434, 19431188, 26896183, 8755918, 30549301, 9463314, 15928302). ClinVar contains an entry for this variant (Variation ID: 3022). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Ataxia - telangiectasia variant Pathogenic:1
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not provided Pathogenic:1
Observed in an individual with early-onset breast cancer (Akbar et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22529920, 23532176, 8789452, 27304073, 11826028, 15279807, 30665703, 17855419, 35710434, 25040471, 26896183, 30549301, 8755918, 19431188, 9000145) -
Hereditary cancer-predisposing syndrome Pathogenic:1
This missense variant replaces phenylalanine with cysteine at codon 2827 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes ATM protein to be unstable, resulting in a reduced kinase activity and DNA damage response (PMID: 19431188, 25040471). This variant has been observed in an individual affected with breast cancer (Color internal data). This variant has been reported in at least two individuals affected with mild form of autosomal recessive ataxia-telangiectasia in compound heterozygous state with a pathogenic truncation variant (PMID: 8755918, 9000145, 9463314, 15928302, 25040471, 30549301), indicating that this variant contributes to disease and appears to be hypomorphic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. Medical management should be considered based on the individual’s personal and family history. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at