NM_000051.4:c.2771G>A

Variant names:

• chr11-108268542-G-A
• rs587782298
• NM_000051.4:c.2771G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):​c.2771G>A​(p.Arg924Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000417 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 4.52

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18398198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2771G>A	p.Arg924Gln	missense_variant	Exon 18 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2771G>A	p.Arg924Gln	missense_variant	Exon 18 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251440 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 727192

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Oct 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R924Q variant (also known as c.2771G>A), located in coding exon 17 of the ATM gene, results from a G to A substitution at nucleotide position 2771. The arginine at codon 924 is replaced by glutamine, an amino acid with highly similar properties. This alteration was observed with an allele frequency of 0.00113 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00089 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0011 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in a breast cancer patient from Uganda (Adedokun B et al. Cancer Epidemiol. Biomarkers Prev. 2020 02;29:359-367). This alteration has also been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46) and in 1/29 ovarian cancer patients in a Japanese cohort (Tomioka K el al. Sci Rep 2021 10;11(1):19661). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 06, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2771G>A, located in exon 18 of the ATM gene, is predicted to result in the substitution of threonine by alanine at codon 924, p.(Arg924Gln). This variant is found in 12/30526 at a filter allele frequency of 0.023% in the gnomAD v2.1.1 database (South Asian non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.308) is indeterminate regarding the effect on protein function. To our knowledge, functional studies have not been reported for this variant. In addition, it has been reported in ClinVar (10x uncertain significance) and LOVD (3x VUS, 2x not provided, 1x likely benign) databases. Based on currently available information, the variant c.2771G>A is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version 1.1. -

Jan 07, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 924 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 19781682, 30287823, 31871109, 32068069, 33471991) and in unaffected individuals (PMID: 30287823, 33471991). This variant has been identified in 19/251440 chromosomes 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:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 924 of the ATM protein (p.Arg924Gln). This variant is present in population databases (rs587782298, gnomAD 0.04%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19781682, 30287823, 31871109, 32068069). ClinVar contains an entry for this variant (Variation ID: 142194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -

Mar 20, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Nov 24, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 26314984, 27105424, 30287823, 31871109) -

not specified Uncertain:1

Feb 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.2771G>A (p.Arg924Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 303700 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.2771G>A has been reported in the literature in individuals affected with Breast Cancer (e.g., Tavtigian_2009, Momozawa_2018, Adedokun_2020, Kwong_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 30287823, 31871109, 32068069, 36243179). ClinVar contains an entry for this variant (Variation ID: 142194). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Microcephaly Uncertain:1

-

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1

Apr 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.2771G>A variant is predicted to result in the amino acid substitution p.Arg924Gln. This variant was reported in individuals with breast/biliary tract cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table SD1, Momozawa et al. 2018. PubMed ID: 30287823; Tbale S1, Adedokun et al. 2019. PubMed ID: 31871109; Table S2, Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142194/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial colorectal cancer type X Uncertain:1

Dec 23, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1

Aug 24, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	.;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;.
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.33	T;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.52	.;P;P
Vest4		0.37, 0.42
MVP		0.90
MPC		0.21
ClinPred		0.091	T
GERP RS		5.7
Varity_R		0.46
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782298; hg19: chr11-108139269; COSMIC: COSV53746095;