11-108227875-G-T

Variant names:

• chr11-108227875-G-T
• rs876660661
• NM_000051.4:c.172G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000051.4(ATM):​c.172G>T​(p.Asp58Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108227875-G-T is Pathogenic according to our data. Variant chr11-108227875-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233820.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.172G>T	p.Asp58Tyr	missense_variant	Exon 3 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.172G>T	p.Asp58Tyr	missense_variant	Exon 3 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726154

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Feb 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with tyrosine at codon 58 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000278275.6). In addition, RNAseq studies showed abnormal splicing that resulted in a premature stop codon as well as some full-length transcript (PMID: 35806449). This variant has been reported in an individual affected with breast cancer (PMID: 35806449). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 10, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>T variant (also known as p.D58Y), located in coding exon 2 of the ATM gene, results from a G to T substitution at nucleotide position 172. The aspartic acid at codon 58 is replaced by tyrosine, an amino acid with highly dissimilar properties. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Ataxia-telangiectasia syndrome Pathogenic:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 58 of the ATM protein (p.Asp58Tyr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35806449). ClinVar contains an entry for this variant (Variation ID: 233820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 35806449; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Uncertain:1

May 15, 2022

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM:c.172G>T variant is absent from the large population studies (GnomAd). The variant is predicted to create a de novo donor splice site in exon 3 by in silico splicing tools. Functional RNA study has shown that the variant causes an incomplete splicing aberration that causes the creation of a premature stop codon (PMID: 35806449). Additionally, the variant also produced a slightly expressed full-length transcript. Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PM2-supp, PP3, PS3-m) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T;.;T;T;T;T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.5	.;M;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;.;D;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;.;.;D;D
Polyphen		1.0	.;D;.;.;.;D;D;D;D;D;.
Vest4		0.82, 0.85, 0.86, 0.87
MutPred		0.45		Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);Gain of MoRF binding (P = 0.0573);
MVP		0.93
MPC		0.53
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -2
DS_DL_spliceai		0.20		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660661; hg19: chr11-108098602;