rs763457172
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):c.4910A>G(p.Asp1637Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000051.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4910A>G | p.Asp1637Gly | missense_variant, splice_region_variant | Exon 33 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250734Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135594
GnomAD4 exome AF: 0.0000746 AC: 109AN: 1461082Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 81AN XY: 726868
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74372
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
a variant of uncertain significance was detected in the ATM gene (Asp1637Gly). This sequence change replaces aspartic acid with glycine at codon 1637 of the ATM protein (p.Asp1637Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs763457172, ExAC 0.08%). This variant has been observed in an individual affected with breast and/or ovarian cancer in a study of 1000 indian families (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 407499) with 4 submissions: 1 benign and 3 variant of uncertain significance. In-silico predictions show benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 1 pathogenic prediction from FATHMM-MKL and the position is not strongly conserved. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene are associated with susceptibility to breast cancer (OMIM 114480 ). -
A heterozygous splice site proximal missense variation in exon 33 of the ATM gene that results in the amino acid substitution of Glycine for Aspartic Acid at codon 1637 (p.Asp1637Gly) was detected. The observed variation has previously been reported in breast and/or ovarian cancer patients [PMID: 29470806, 30093976]. The p.Asp1637Gly variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in-silico predictions of the variant are benign by PolyPhen-2 (Hum_Div), SIFT, LRT and Mutation Taster2 tools. The reference codon is conserved in mammals. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
The missense c.4910A>G (p.Asp1637Gly) in ATM gene has been reported in heterozygous state in multiple individuals affected with Breast cancer, susceptibility (Tsaousis et. al., 2019; Chan et. al., 2018; Singh et. al., 2018). The p.Asp1637Gly variant is present with allele frequency of 0.01% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The reference amino acid at this position on ATM gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 1637 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
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Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
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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. -
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Ataxia-telangiectasia syndrome Uncertain:2Benign:1
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not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at