chr11-108333946-T-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_000051.4(ATM):āc.7988T>Cā(p.Val2663Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,611,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. V2663F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7988T>C | p.Val2663Ala | missense_variant | 54/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.7988T>C | p.Val2663Ala | missense_variant | 54/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251198Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135758
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1458834Hom.: 0 Cov.: 30 AF XY: 0.00000964 AC XY: 7AN XY: 725904
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74490
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 12, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 03, 2023 | 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]. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2023 | The p.V2663A variant (also known as c.7988T>C), located in coding exon 53 of the ATM gene, results from a T to C substitution at nucleotide position 7988. The valine at codon 2663 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 23, 2016 | - - |
not specified Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2023 | Variant summary: ATM c.7988T>C (p.Val2663Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251198 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia Telangiectasia or Breast Cancer, allowing no conclusion about variant significance. c.7988T>C has been reported in the literature in at-least one individual affected with Breast Cancer (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26976419). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Likely benign, n=3; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history with breast and other cancers (Tung et al., 2016; Yehia et al., 2018; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 24728327, 26976419, 30171174, 26193622, 32832836) - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2023 | The ATM c.7988T>C variant is predicted to result in the amino acid substitution p.Val2663Ala. This variant has been reported individuals with breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Table S2, Wilson et al. 2019. PubMed ID: 30171174), unspecified cancer types (Table S9, Yehia et al. 2018. PubMed ID: 29684080), and inflammatory bowel disease (Table S2, Kelsen et al. 2015. PubMed ID: 26193622). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108204673-T-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133635/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at