rs143577586
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000051.4(ATM):c.5728C>A(p.Leu1910Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,684 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1910F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5728C>A | p.Leu1910Ile | missense_variant | 38/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.5728C>A | p.Leu1910Ile | missense_variant | 38/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251114Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135724
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461514Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 727058
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1910 of the ATM protein (p.Leu1910Ile). This variant is present in population databases (rs143577586, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer and/or male breast cancer (PMID: 28135145, 30613976). ClinVar contains an entry for this variant (Variation ID: 185625). 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. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2022 | The p.L1910I variant (also known as c.5728C>A), located in coding exon 37 of the ATM gene, results from a C to A substitution at nucleotide position 5728. The leucine at codon 1910 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095) and in one individual from an Italian cohort of male breast cancer patients enriched for non-BRCA1/2 cases (Rizzolo P et al. Int J Cancer 2019 07;145(2):390-400). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 | Dec 23, 2021 | This missense variant replaces leucine with isoleucine at codon 1910 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 2/251114 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 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 colorectal or male breast cancer in published literature (Yurgelun et al., 2017; Rizzolo et al., 2019); This variant is associated with the following publications: (PMID: 30613976, 28135145) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at