rs587782310
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000051.4(ATM):c.7328G>A(p.Arg2443Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,012 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2443G) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7328G>A | p.Arg2443Gln | missense_variant | 50/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7328G>A | p.Arg2443Gln | missense_variant | 50/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251134Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135722
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727194
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 02, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 22, 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; Identified in individuals with breast or ovarian cancer (Hauke 2018, Singh 2018); This variant is associated with the following publications: (PMID: 17344846, 25344691, 22072542, 28263231, 29522266, 30287823, 31754145, 16461462, 24356096, 27043212, 27175599, 30814645, 30972172, 31740029, 29470806, 23532176, 26630574, 32522261) - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2443 of the ATM protein (p.Arg2443Gln). This variant is present in population databases (rs587782310, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 29470806, 29522266). ClinVar contains an entry for this variant (Variation ID: 142211). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2023 | The p.R2443Q variant (also known as c.7328G>A), located in coding exon 49 of the ATM gene, results from a G to A substitution at nucleotide position 7328. The arginine at codon 2443 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0.00 in 7051 unselected breast cancer patients and 0.00009 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This alteration was detected in a cohort of 72 hereditary breast/ovarian cancer cases and 57 hereditary non-polyposis colon cancer cases from Spain (Velázquez C et al. J Transl Med, 2020 Jun;18:232). 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 | Sep 25, 2020 | This missense variant replaces arginine with glutamine at codon 2443 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 an individual affected with breast cancer (PMID: 29522266). This variant has been identified in 3/282544 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. - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 04, 2021 | The ATM c.7328G>A (p.Arg2443Gln) variant is a missense variant that has been reported in one study, in which it was found in a presumably heterozygous state in a female with breast cancer (Hauke et al. 2018). The variant was absent from 2189 controls in the study but is reported at a frequency of 0.000011 in the Total population of the Genome Aggregation Database. Functional studies are not available and in silico tools provide conflicting predictions for this variant. Based on the limited evidence, the p.Arg2443Gln variant is classified as a variant of uncertain significance for ATM-related disorders. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at