rs863224573

Variant names:

• chr11-108243953-A-G
• rs863224573
• NM_000051.4:c.497A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108243953-A-G
• chr11-108243953-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP6

The NM_000051.4(ATM):​c.497A>G​(p.Glu166Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E166D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.4623
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108235834-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 627570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 11-108243953-A-G is Benign according to our data. Variant chr11-108243953-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 643645.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.497A>G	p.Glu166Gly	missense_variant, splice_region_variant	Exon 6 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.497A>G	p.Glu166Gly	missense_variant, splice_region_variant	Exon 6 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Apr 08, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 643645). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 166 of the ATM protein (p.Glu166Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Hereditary cancer-predisposing syndrome Benign:1

Dec 06, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.52	T;T;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	.;L;L
PhyloP100		5.9
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.13
Sift	Benign	0.032	D;D;D
Sift4G	Benign	0.097	T;T;T
Polyphen		0.20	.;B;B
Vest4		0.52, 0.57
MutPred		0.40		Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);
MVP		0.97
MPC		0.16
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.29
gMVP		0.27
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.55
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

Other links and lift over

dbSNP: rs863224573; hg19: chr11-108114680;