rs529296539
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PM5BS2
The NM_000051.4(ATM):c.8495G>A(p.Arg2832His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,710 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R2832S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.8495G>A | p.Arg2832His | missense | Exon 58 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.8495G>A | p.Arg2832His | missense | Exon 59 of 64 | NP_001338763.1 | |||
| C11orf65 | NM_001330368.2 | c.641-36748C>T | intron | N/A | NP_001317297.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.8495G>A | p.Arg2832His | missense | Exon 58 of 63 | ENSP00000501606.1 | ||
| ATM | ENST00000452508.7 | TSL:1 | c.8495G>A | p.Arg2832His | missense | Exon 59 of 64 | ENSP00000388058.2 | ||
| ATM | ENST00000527805.6 | TSL:1 | n.*3559G>A | non_coding_transcript_exon | Exon 56 of 61 | ENSP00000435747.2 |
Frequencies
GnomAD3 genomes 0.0000921 AC: 14AN: 152054Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000119 AC: 30AN: 251276 AF XY: 0.000103 show subpopulations
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461538Hom.: 2 Cov.: 30 AF XY: 0.000100 AC XY: 73AN XY: 727062 show subpopulations
Age Distribution
GnomAD4 genome 0.0000920 AC: 14AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74412 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:5
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2832 of the ATM protein (p.Arg2832His). This variant is present in population databases (rs529296539, gnomAD 0.05%). This missense change has been observed in individual(s) with lung, breast or ovarian and pancreatic cancer (PMID: 26689913, 28726808, 28779002, 30303537, 33552952). ClinVar contains an entry for this variant (Variation ID: 133638). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. This variant disrupts the p.Arg2832 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9443866, 10817650, 10873394, 12552559, 18634022). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
The ATM p.Arg2832His variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs529296539) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and two other submitters). The variant was identified in control databases in 31 of 276996 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), Latino in 1 of 34388 chromosomes (freq: 0.00003), European in 9 of 126562 chromosomes (freq: 0.00007), East Asian in 4 of 18866 chromosomes (freq: 0.0002), and South Asian in 16 of 30774 chromosomes (freq: 0.0005), while the variant was not observed in the Other, Ashkenazi Jewish, or Finnish populations. The p.Arg2832 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
not provided Uncertain:4
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, or other cancers (Lu et al., 2015; Decker et al., 2017; Chaffee et al., 2018; Girard et al., 2019; Kadri et al., 2020; Castillo-Guardiola et al., 2022; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 27198204, 18634022, 24728327, 24841718, 26689913, 28779002, 29338072, 28726808, 29641532, 28652578, 33552952, 31422574, 32736562, 36480066, 14706517, 20305132, 35273907, 33471991, 34720947, 34174931, 21665257, 30093976, 35130390, 35085662, 23532176, 30303537, 35245693, 35264596)
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022), 33552952 (2020), 30303537 (2019), 28779002 (2017), 26689913 (2015), 20305132 (2010)), pancreatic cancer (PMID: 28726808 (2018)), and lung cancer (PMID: 26689913 (2015)). This variant has also been reported in unaffected individuals (PMID: 31422574 (2019), 29641532 (2018), 28652578 (2017), 24728327 (2014)). The frequency of this variant in the general population, 0.00049 (15/30602 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Hereditary cancer-predisposing syndrome Uncertain:3
The p.R2832H variant (also known as c.8495G>A), located in coding exon 57 of the ATM gene, results from a G to A substitution at nucleotide position 8495. The arginine at codon 2832 is replaced by histidine, an amino acid with highly similar properties. A different missense alteration affecting the same amino acid, p.R2832C, has been reported as pathogenic by multiple groups (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Becker-Catania S et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). The p.R2832H alteration was identified in 1/1358 non-cancer control individuals and was not observed in 57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was identified in 1/1207 cases of BRCA negative French women was not observed in 1199 general population controls; this variant was also observed once in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration has also been identified 1/302 individuals with pancreatic cancer (Chaffee KG et al. Genet Med, 2018 01;20:119-127). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This missense variant replaces arginine with histidine at codon 2832 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20305132, 30303537, 33552952, 35264596, 38896321), pancreatic cancer (PMID: 28726808) and gastric cancer (PMID: 14706517), as well as in unaffected individuals (PMID: 24728327, 31422574). In a large breast cancer case-control study, this variant was observed in 9/60457 cases and 3/53458 controls, showing inconclusive association with disease (OR=2.653, 95%CI 0.718 to 9.799, p-value=0.155; PMID: 33471991). This variant has been identified in 31/282644 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same position, p.Arg2832Cys and p.Arg2832Pro, are considered to be disease-causing (ClinVar variation ID: 127459, 429065), suggesting that the arginine amino acid at this position is important for the protein function. 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 specified Uncertain:2Other:1
Variant summary: ATM c.8495G>A (p.Arg2832His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) and ATM, catalytic domain (IPR044107) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251276 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00012 vs 0.001), allowing no conclusion about variant significance. c.8495G>A has been reported in the literature in individuals affected with various forms of cancer including gastric, pancreatic, breast, and lung cancer (e.g., Zhang_2004, Chaffee_2018, Girard_2019, Guindalini_2022, Bernstein_2010, Castillo-Guardiola_2022, Lu_2015). However the variant has also been detected in healthy control individuals (e.g., Bodian_2014, Tiao_2017). These data therefore do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon (c.8494C>T/p.Arg2832Cys) has been reported as pathogenic in ClinVar (CV ID 127459) and is associated with several types of cancer (HGMD). The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 24728327, 35245693, 28726808, 30303537, 35264596, 26689913, 28652578, 30374176, 14706517). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=12) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Breast and/or ovarian cancer Uncertain:1
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Familial cancer of breast Uncertain:1
The ATM c.8495G>A (p.Arg2832His) missense change has a maximum subpopulation frequency of 0.049% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 20305132), gastric cancer (PMID: 14706517), and pancreatic cancer (PMID: 28726808), and it has also been observed in control subjects (PMID: 24728327, 30303537, 31422574). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). Missense variants affecting the same amino acid residue, p.Arg687Cys, and p.Arg687Pro, have been reported as pathogenic in individuals with ataxia telangiectasia (PMID: 9443866, 10817650, 10873394, 18634022). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ovarian cancer Benign:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at