11-108321345-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000051.4(ATM):c.6497T>C(p.Val2166Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,034 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 Uncertain significance (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6497T>C | p.Val2166Ala | missense_variant | Exon 45 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251450Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135890
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727240
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74332
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2166 of the ATM protein (p.Val2166Ala). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individual(s) with ATM-related conditions (PMID: 30287823, 33436325, 35171259). ClinVar contains an entry for this variant (Variation ID: 489574). 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. -
- -
not provided Uncertain:2
ATM: PM2 -
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 24807215, 33436325, 30287823, 29338689, 23532176, 32566746, 35171259, 36243179, 31214711) -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces valine with alanine at codon 2166 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 cancer and pancreatic ductal adenocarcinoma, as well as in unaffected individuals (PMID: 30287823, 33471991, 35171259). This variant has been identified in 10/282848 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. -
The p.V2166A variant (also known as c.6497T>C), located in coding exon 44 of the ATM gene, results from a T to C substitution at nucleotide position 6497. The valine at codon 2166 is replaced by alanine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00065 in 7636 unselected prostate cancer patients and 0.00073 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This variant was reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
not specified Uncertain:1
Variant summary: ATM c.6497T>C (p.Val2166Ala) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 0.0001 in 298912 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.0001 vs 0.001), allowing no conclusion about variant significance. c.6497T>C has been reported in the literature in individuals affected with, prostate cancer, pancreatic ductal adenocarcinoma or biliary tract cancers (Karlson_2021, Yin_2022, Okawa_2023) and breast cancer, but also in healthy controls (e.g. Momozawa_2018). 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: 33436325, 30287823, 36243179, 35171259). ClinVar contains an entry for this variant (Variation ID: 489574). Based on the evidence outlined above, the variant was classified as uncertain significance. -
ATM-related disorder Uncertain:1
The ATM c.6497T>C variant is predicted to result in the amino acid substitution p.Val2166Ala. This variant has been reported in cases and controls from a breast cancer cohort study (Supplement, Momozawa et al. 2018. PubMed ID: 30287823). It has also been reported in individuals with prostate cancer (Table S6, Momozawa et al. 2020. PubMed ID: 31214711; Table S4, Karlsson et al. 2021. PubMed ID: 33436325). This variant is reported in 0.036% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108192072-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/489574/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial cancer of breast Uncertain:1
- -
Hereditary breast ovarian cancer syndrome Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at