rs56353517
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_000051.4(ATM):c.2220A>G(p.Ala740=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,611,432 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A740A) has been classified as Likely benign.
Frequency
Consequence
NM_000051.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2220A>G | p.Ala740= | synonymous_variant | 14/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2220A>G | p.Ala740= | synonymous_variant | 14/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251244Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135808
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1459134Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 725938
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74476
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2015 | 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2019 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
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.Ala740= variant was identified in 1 of 14102 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and was identified in 5 of 24980 control chromosomes (frequency: 0.0002) from healthy men individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs56353517) as "With Likely benign allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, Color and Counsyl), and in LOVD 3.0 (2x). The variant was identified in control databases in 25 of 277006 chromosomes (1 homozygous) at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 25 of 18816 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ala740= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) 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. - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at