rs750897021
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000051.4(ATM):c.2012T>A(p.Ile671Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. I671V) 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.2012T>A | p.Ile671Lys | missense_variant | 13/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2012T>A | p.Ile671Lys | missense_variant | 13/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251404Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461792Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727198
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 671 of the ATM protein (p.Ile671Lys). This variant is present in population databases (rs750897021, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 34196900). ClinVar contains an entry for this variant (Variation ID: 185852). 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 tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. | Feb 26, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2023 | The p.I671K variant (also known as c.2012T>A), located in coding exon 12 of the ATM gene, results from a T to A substitution at nucleotide position 2012. The isoleucine at codon 671 is replaced by lysine, an amino acid with dissimilar properties. This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This amino acid position is poorly 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 | Spanish ATM Cancer Susceptibility Variant Interpretation Working Group | Jun 17, 2020 | The c.2012T>A (p.Ile671Lys) variant has an allele frequency of 0.0000084 (0.0008%, 2/ 236,866 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00005838 (0.006%, 2/34,260 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE. A new acceptor site is created/activated, according to SSF and MaxEnt, but its score does not exceed the natural one. Furthermore, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting information to consider any other evidence. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules were applied as defined by the Spanish-ATM Variant Curation Panel: BP4 (PMID: 33280026). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at