11-108282876-A-T

Variant names:

• chr11-108282876-A-T
• rs766226370
• NM_000051.4:c.3743A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000051.4(ATM):​c.3743A>T​(p.Tyr1248Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000753 in 1,328,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1248H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.99
• Publications: 6 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33157766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3743A>T	p.Tyr1248Phe	missense_variant	Exon 25 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3743A>T	p.Tyr1248Phe	missense_variant	Exon 25 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.53e-7 AC: 1 AN: 1328466 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 666864

African (AFR) AF: 0.00 AC: 0 AN: 30178

American (AMR) AF: 0.00 AC: 0 AN: 42350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25022

East Asian (EAS) AF: 0.00 AC: 0 AN: 38814

South Asian (SAS) AF: 0.00 AC: 0 AN: 82498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5346

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995598

Other (OTH) AF: 0.00 AC: 0 AN: 55778

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3743A>T (p.Y1248F) alteration is located in exon 25 (coding exon 24) of the ATM gene. This alteration results from a A to T substitution at nucleotide position 3743, causing the tyrosine (Y) at amino acid position 1248 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dec 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with phenylalanine at codon 1248 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. 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. -

Ataxia-telangiectasia syndrome Uncertain:1

Jan 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1248 of the ATM protein (p.Tyr1248Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 834536). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.095	.;T;T
Eigen	Benign	0.0023
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	.;M;M
PhyloP100		5.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.13	T;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.66	.;P;P
Vest4		0.49
MutPred		0.34		Loss of methylation at K1253 (P = 0.0537);Loss of methylation at K1253 (P = 0.0537);Loss of methylation at K1253 (P = 0.0537);
MVP		0.82
MPC		0.11
ClinPred		0.77	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.32
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs766226370; hg19: chr11-108153603;