rs34099398
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000051.4(ATM):c.7999A>G(p.Met2667Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,608,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M2667L) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7999A>G | p.Met2667Val | missense_variant | 54/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7999A>G | p.Met2667Val | missense_variant | 54/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151906Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135712
GnomAD4 exome AF: 0.0000268 AC: 39AN: 1456168Hom.: 0 Cov.: 30 AF XY: 0.0000235 AC XY: 17AN XY: 724744
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151906Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74222
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 18, 2024 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 23, 2022 | - - |
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2667 of the ATM protein (p.Met2667Val). This variant is present in population databases (rs34099398, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer or breast cancer (PMID: 19781682, 28135145). ClinVar contains an entry for this variant (Variation ID: 141559). 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. 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 18, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 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 with a reportedly pathogenic ATM variant, phase (cis or trans) unknown, in a patient with colorectal cancer (Yurgelun et al., 2017); Observed in individuals with breast cancer, but also in healthy controls (Renwick et al., 2006; Tavtigian et al., 2009; Bhai et al., 2021); This variant is associated with the following publications: (PMID: 26787654, 26727500, 22529920, 33471991, 16832357, 34326862, 19781682, 28135145) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2023 | The p.M2667V variant (also known as c.7999A>G), located in coding exon 53 of the ATM gene, results from an A to G substitution at nucleotide position 7999. The methionine at codon 2667 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in multiple breast cancer cohorts as well and unaffected control groups across studies (Renwick A et al. Nat Genet, 2006 Aug;38:873-5; Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46; Young EL et al. J Med Genet, 2016 06;53:366-76; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been reported in an individual affected with colorectal cancer, who was also identified to carry a pathogenic mutation in ATM (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 27, 2021 | This missense variant replaces methionine with valine at codon 2667 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 unaffected individuals (PMID: 16832357, 19781682, 33471991; Color Health internal data). This variant also has been reported in an individual affected with colorectal cancer, although the individual was found to also have a co-occuring ATM germline mutation (PMID: 28135145). This variant has been identified in 4/282418 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 02, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at