11-108250981-G-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting
The NM_000051.4(ATM):c.1516G>T(p.Gly506Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000459 in 1,613,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G506G) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1516G>T | p.Gly506Cys | missense_variant | Exon 10 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152110Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000398 AC: 10AN: 251234 AF XY: 0.0000589 show subpopulations
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461832Hom.: 1 Cov.: 35 AF XY: 0.0000481 AC XY: 35AN XY: 727214 show subpopulations
GnomAD4 genome 0.0000329 AC: 5AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74308 show subpopulations
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
The p.G506C variant (also known as c.1516G>T), located in coding exon 9 of the ATM gene, results from a G to T substitution at nucleotide position 1516. The glycine at codon 506 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported as homozygous in a Saudi female with onset of ataxia telangiectasia (A-T) at age 14 with classic neurodegenerative symptoms clinically and on imaging but without immune system dysfunction or endocrine abnormalities. Another affected sister was also homozygous for this alteration, while three heterozygous family members did not have features of A-T (Algahtani H et al. Int J Neurosci, 2020 Mar;:1-6). This variant has also been identified in individuals with breast cancer and in one proband with cutaneous melanoma (Decker B et al. J Med Genet, 2017;54:732-741; Hauke J et al. Cancer Medicine, 2018;7(4):1349-1358; Pastorino L et al. Cancers, 2020 04;12(4):1007; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22). This alteration was seen in a total of 11/61,198 breast cancer cases as well as 6/53,951 controls across two studies (Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). In another study, this alteration was reported in the germline of 5 of 8,920 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 amino acid position is not 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. -
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This missense variant replaces glycine with cysteine at codon 506 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 an individual with bilateral breast cancer (PMID: 34299313). In a large international case-control study, this variant was reported in 8/60458 breast cancer cases and 4/53457 controls (OR=1.768, 95%CI 0.532 to 5.873, p-value=0.399; PMID: 33471991). A report by Algahtani et al, 2021 (PMID: 32172615) identified this variant in the homozygous state in a Saudi female with onset of atypical ataxia-telangiectasia at 14 years old. This individual had slow disease progression with neurodegenerative symptoms but no immune system deficiencies and normal endocrine function. Her sister was also homozygous for this variant and exhibited similar atypical ataxia-telangiectasia symptoms with disease onset at 16 years old. Their parents were first degree cousin, had no symptoms, and were heterozygous for this variant. The proband had 8 unaffected siblings, one of whom was genotyped and shown to be heterozygous for this variant. This variant has also been identified in 11/282626 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. -
Ataxia-telangiectasia syndrome Uncertain:2Benign:1
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not provided Uncertain:2Benign:1
This variant is associated with the following publications: (PMID: 25318351, 27997549, 26786923, 32172615, 24123366, 28652578, 32325837) -
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not specified Uncertain:1Benign:1
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1516G>T, in exon 10 that results in an amino acid change, p.Gly506Cys. This sequence change does not appear to have been previously described in patients with ATM-related disorders and has been described in the gnomAD database with a frequency of 0.007% in the European sub-population (dbSNP rs587779816). The p.Gly506Cys change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Gly506Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly506Cys change remains unknown at this time. -
Variant summary: ATM c.1516G>T (p.Gly506Cys) 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 0.00004585 in 1613942 control chromosomes, predominantly at a frequency of 0.005095 within the Middle Eastern subpopulation in the gnomAD v4 database, including one homozygote. The observed variant frequency within Middle Eastern control individuals in the gnomAD database is approximately 1.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Middle Eastern origin. c.1516G>T has been reported in the literature in individuals affected with different types of cancer (Algahtani_2020, Pastorino_2020, Dalmasso_2021, de Oliveira_2022, AlHarbi_2023, Lima_2023). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5251C>T, p.Arg1751*; MSH2 c.862C>T, p.Gln288*), providing supporting evidence for a benign role (AlHarbi_2023). 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: 37306523, 32172615, 34262154, 37529773, 32325837, 35534704). ClinVar contains an entry for this variant (Variation ID: 127339). Based on the evidence outlined above, the variant was classified as likely benign. -
Breast and/or ovarian cancer Uncertain:1
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ATM-related cancer predisposition Uncertain:1
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Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.1516G>T variant is predicted to result in the amino acid substitution p.Gly506Cys. This variant has been reported in the homozygous state in two siblings with ataxia telangiectasia (Algahtani et al. 2021. PubMed ID: 32172615). This variant has been reported in patients with colorectal, breast or ovarian cancer, and melanoma (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; File S2, Howitt et al. 2014. PubMed ID: 25231023; Cock-Rada et al. 2018. PubMed ID: 28528518, Pastorino et al. 2020. PubMed ID: 32325837), but was also reported in three healthy control individuals in a study of patients with chronic lymphocytic leukemia (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108121708-G-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127339/). 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
a variant of uncertain significance in the ATM gene (p.Gly506Cys). This sequence change replaces glycine with cysteine at codon 506 of the ATM protein (p.Gly506Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant has been reported in the literature in individuals with ATM-related disease (PMID 32172615, 32325837). ClinVar contains an entry for this variant (Variation ID: 127339) with 6 submissions: 1 likely benign and 5 uncertain significance, conflicting interpretations. In-silico predictions for this varint show Pathogenic computational verdict based on 7 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from BayesDel_addAF, DEOGEN2, LIST-S2, MVP and PrimateAI. for these reasons, this variant has been classified as a Variant of Uncertain Significance. Pathogenic mutations in the ATM gene cause autosomal dominant Susceptibility to Breast Cancer (OMIM 114480). -
Hereditary breast ovarian cancer syndrome Uncertain:1
According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: PM3 (supporting pathogenic): Algahtani (2021, PMID: 32172615): reported homozygoues in female + sister with late-onset AT --> 2P (Phenotype consistent & homozygous occurence) -
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1
The ATM:c.1516G>T (p.Gly506Cys) variant is a rare missense change located in exon 10 of the ATM gene, affecting a moderately conserved glycine residue in the N-terminal region of the protein. Computational prediction tools consistently indicate a likely benign impact on protein function. Based on the concordant in silico evidence and the lack of indications of pathogenicity, this variant is classified as likely benign according to ACMG/AMP guidelines. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at