11-108365126-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.8895G>C(p.Leu2965Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8895G>C | p.Leu2965Phe | missense_variant | Exon 62 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251402Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces leucine with phenylalanine at codon 2965 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on 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 (PMID: 21787400, 29522266). In an international breast cancer case-control meta-analysis, this variant was detected in 1/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251402 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.L2965F variant (also known as c.8895G>C), located in coding exon 61 of the ATM gene, results from a G to C substitution at nucleotide position 8895. The leucine at codon 2965 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). This variant was reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a study assessing 76 rare sequence variants in the ATM gene, variants were grouped into three categories of likely pathogenicity based on in silico analysis and conditional logistic regression, and this alteration was in Group 1, the group containing variants that confer a lower risk of breast cancer than variants classified in Groups 2 or 3 (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). 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. -
not specified Uncertain:1
Variant summary: ATM c.8895G>C (p.Leu2965Phe) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8895G>C has been reported in the literature in individuals affected with breast cancer (Hauke_2018). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Ataxia-telangiectasia syndrome Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2965 of the ATM protein (p.Leu2965Phe). This variant is present in population databases (rs200899512, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 127465). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 27602502). 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:1
This variant is denoted ATM c.8895G>C at the cDNA level, p.Leu2965Phe (L2965F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has been reported in at least two individuals with breast cancer (Hauke 2018). ATM Leu2965Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in FATC Domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Leu2965Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at