rs769980220
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000051.4(ATM):āc.4304A>Cā(p.Lys1435Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,612,838 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1435Q) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4304A>C | p.Lys1435Thr | missense_variant | 29/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4304A>C | p.Lys1435Thr | missense_variant | 29/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250358Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135358
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460616Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 726582
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 11, 2022 | This missense variant replaces lysine with threonine at codon 1435 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 and in an unaffected individual (PMID: 28779002). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/250358 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2024 | The p.K1435T variant (also known as c.4304A>C), located in coding exon 28 of the ATM gene, results from an A to C substitution at nucleotide position 4304. The lysine at codon 1435 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not well 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 | curation | Sema4, Sema4 | Feb 17, 2022 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2023 | Variant summary: ATM c.4304A>C (p.Lys1435Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4304A>C has been reported in the literature in individuals affected with Breast Cancer or hematologic malignancies including chronic lymphocytic leukemia without strong evidence for causality (example, Dorling_2021, Lampson_2023). This variant has also been reported in a publication but is unclear whether it was observed in controls and/or Breast Cancer patients (Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28779002, 36315919, 33471991). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2018 | This variant is denoted ATM c.4304A>C at the cDNA level, p.Lys1435Thr (K1435T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has been observed in breast cancer cases as well as an unaffected control (Decker 2017). ATM Lys1435Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This very is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys1435Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at