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

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

19
Splicing: ADA: 0.00004949
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3

Conservation

PhyloP100: 1.62
Variant links:
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02469322).
BP6
Variant 11-108297287-A-G is Benign according to our data. Variant chr11-108297287-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407499.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.4910A>G p.Asp1637Gly missense_variant, splice_region_variant Exon 33 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.4910A>G p.Asp1637Gly missense_variant, splice_region_variant Exon 33 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00165
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
27
AN:
250734
Hom.:
0
AF XY:
0.000162
AC XY:
22
AN XY:
135594
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000882
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000746
AC:
109
AN:
1461082
Hom.:
0
Cov.:
30
AF XY:
0.000111
AC XY:
81
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00121
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00165
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.000107
AC:
13

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:4
May 30, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 ). -

Feb 06, 2024
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 22, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Feb 20, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Dec 10, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Mar 31, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 23, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2018
GeneKor MSA
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:2Benign:1
Dec 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 04, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 28, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Mar 17, 2022
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.070
T;T
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.67
T;.
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.025
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.66
N;N
REVEL
Benign
0.031
Sift
Benign
0.18
T;T
Sift4G
Benign
0.29
T;T
Polyphen
0.0
B;B
Vest4
0.18
MutPred
0.31
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.71
MPC
0.16
ClinPred
0.036
T
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.090
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000049
dbscSNV1_RF
Benign
0.0020
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763457172; hg19: chr11-108168014; API