11-108252894-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.1880T>G(p.Phe627Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,612,246 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.1880T>G | p.Phe627Cys | missense_variant | Exon 12 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250808Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135578
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1459934Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726392
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:3Other:1
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Variant interpretted as Uncertain significance and reported on 12-16-2019 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11996792, 19781682, 12935922, 28779002) -
The ATM c.1880T>G; p.Phe627Cys variant (rs546087885), is reported in the literature in individuals affected with breast cancer (Bernstein 2010, Sommer 2002, Tavtigian 2009). This variant is also reported in ClinVar (Variation ID: 232928). It is only found on four alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.338). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bernstein JL et al. Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. J Natl Cancer Inst. 2010 Apr 7;102(7):475-83. PMID: 20305132. Sommer SS et al. Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. Cancer Genet Cytogenet. 2002 Apr 1;134(1):25-32. PMID: 11996792. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-46. PMID: 19781682. -
Ataxia-telangiectasia syndrome Uncertain:3
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 627 of the ATM protein (p.Phe627Cys). This variant is present in population databases (rs546087885, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 11996792, 12935922, 19781682). ClinVar contains an entry for this variant (Variation ID: 232928). 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%. 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. -
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Hereditary cancer-predisposing syndrome Uncertain:2
The p.F627C variant (also known as c.1880T>G), located in coding exon 11 of the ATM gene, results from a T to G substitution at nucleotide position 1880. The phenylalanine at codon 627 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This alteration has been reported in the germline of 2 of 8920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This variant was also identified in a patient with breast cancer (Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83). 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. -
This missense variant replaces phenylalanine with cysteine at codon 627 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 (PMID: 11996792, 12935922, 19781682). In a large international case-control study, this variant was reported in 7/60466 breast cancer cases and 1/53461 controls (OR=6.19, 95%CI 0.761 to 50.312, p-value=0.074; PMID: 33471991). This variant has been identified in 4/282200 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. -
not specified Uncertain:1
Variant summary: ATM c.1880T>G (p.Phe627Cys) results in a non-conservative amino acid change in 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 1.2e-05 in 250808 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1880T>G has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010, Sommer_2003, Tavtigian_2009). 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. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Breast and/or ovarian cancer Uncertain:1
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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