rs786202229
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000051.4(ATM):c.2085G>A(p.Leu695=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L695L) 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 -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2085G>A | p.Leu695= | synonymous_variant | 13/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2085G>A | p.Leu695= | synonymous_variant | 13/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461672Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727128
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 28, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Leu695= variant was identified in 2 of 5526 proband chromosomes (frequency: 0.00018) from individuals or families with breast cancer (Bernstein_2010, Rosenstein_2006). The variant was also identified in dbSNP (ID: rs786202229) as “With Likely benign allele”, ClinVar (as likely benign by Ambry Genetics, Invitae, and Color Genomics and as uncertain significance by Integrated Genetics), and Clinvitae (2x). The variant was not identified in the Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1 of 30948 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). It was observed in the “Other” population in 1 of 980 chromosomes (freq: 0.00102), but not in the African, Latino, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Leu695Leu 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. However, 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a cryptic 3’ splice site; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 29, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 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 | curation | Sema4, Sema4 | Nov 09, 2020 | - - |
Ataxia-telangiectasia syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 23, 2020 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 26, 2021 | - - |
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 | Jun 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at