chr11-108272604-T-C
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000051.4(ATM):c.3150T>C(p.Leu1050=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,613,698 control chromosomes in the GnomAD database, including 11 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. L1050L) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3150T>C | p.Leu1050= | synonymous_variant | 21/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.3150T>C | p.Leu1050= | synonymous_variant | 21/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000907 AC: 138AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00156 AC: 392AN: 251242Hom.: 1 AF XY: 0.00177 AC XY: 240AN XY: 135810
GnomAD4 exome AF: 0.000793 AC: 1159AN: 1461384Hom.: 11 Cov.: 32 AF XY: 0.000944 AC XY: 686AN XY: 727014
GnomAD4 genome AF: 0.000906 AC: 138AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74486
ClinVar
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 29, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 30, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 26, 2018 | Variant summary: The variant, ATM c.3150T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0016 in 277234 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.009 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. The variant c.3150T>C has been reported in the literature in individuals affected with breast or ovarian cancer (Heikkinen_2005). This report, however does not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, an internal sample reports the variant to co-occur with a likely pathogenic RAD51C variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ATM: BP4 - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 31, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2014 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 07, 2015 | - - |
Ataxia-telangiectasia syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Familial cancer of breast Benign:2
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 13, 2024 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 06, 2021 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Leu1050= variant was identified in 1 of 242 proband chromosomes (frequency: 0.004) from Finnish individuals or families with breast and/or ovarian cancer; and was present in 1 of 186 control chromosomes (frequency: 0.005) from lymphoblastoid cell lines from unselected individuals from major populations (Thorstenson 2001, Heikkinen 2005). The variant was also identified in dbSNP (ID: rs3092859) “With Likely benign” allele , ClinVar (classified benign by Invitae and likely benign by Ambry Genetics). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD database. The variant was identified in control databases in 439 (1 homozygous) of 277050 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu1050= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, but located 4 nucleotides from the 3’end of exon 21. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at