chr11-108251977-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.1748A>G(p.Tyr583Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. Y583S) has been classified as Uncertain significance.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1748A>G | p.Tyr583Cys | missense_variant | 11/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.1748A>G | p.Tyr583Cys | missense_variant | 11/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250974Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461412Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727018
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2023 | 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 breast cancer (Decker et al., 2017; Hauke et al., 2018); This variant is associated with the following publications: (PMID: 30287823, 25275298, 29522266, 28779002) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2016 | Variant summary: The ATM c.1748A>G (p.Tyr583Cys) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Tyr583 is not located in any known functional domain and is not highly conserved across species. This variant was found in 1/121140 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was reported to have been identified in one sample from a large panel of HNSCC-derived cells (Martin_Oncotarget_2014), but has not been cited in patients in the literature. In addition, multiple clinical diagnostic laboratories classified this variant as a VUS. In the absence of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 12, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | The p.Y583C variant (also known as c.1748A>G), located in coding exon 10 of the ATM gene, results from an A to G substitution at nucleotide position 1748. The tyrosine at codon 583 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in breast cancer cohorts (Decker B et al. J. Med. Genet. 2017 11;54(11):732-741; Hauke J et al. Cancer Med 2018 04;7(4):1349-1358; Mullins BT et al. Rep Pract Oncol Radiother Nov;24(6):672-680). In one study, this alteration was not observed in 7,051 unselected female breast cancer patients but was observed in 1/11,241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected Japanese male breast cancer patients but was observed in 1/12,490 matched male controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). This amino acid position is not 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces tyrosine with cysteine at codon 583 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 cancer (PMID: 28779002, 29522266, 31719806, 33471991). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 3/53461 controls (PMID: 33471991). This variant has been identified in 4/250974 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
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at