rs759753186

Variant names:

• chr11-108316036-A-G
• rs759753186
• NM_000051.4:c.6121A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108316036-A-G
• chr11-108316036-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000051.4(ATM):​c.6121A>G​(p.Met2041Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. M2041I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.25
• Publications: 1 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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 45 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14025888).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.6121A>G	p.Met2041Val	missense	Exon 42 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6121A>G	p.Met2041Val	missense	Exon 43 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-6965T>C		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6121A>G	p.Met2041Val	missense	Exon 42 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6121A>G	p.Met2041Val	missense	Exon 43 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1185A>G		non_coding_transcript_exon	Exon 40 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251398 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2041 of the ATM protein (p.Met2041Val). This variant is present in population databases (rs759753186, gnomAD 0.01%). 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: 482583). 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.

Hereditary cancer-predisposing syndrome Uncertain:2

Aug 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M2041V variant (also known as c.6121A>G), located in coding exon 41 of the ATM gene, results from an A to G substitution at nucleotide position 6121. The methionine at codon 2041 is replaced by valine, an amino acid with highly similar properties. This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This alteration has also been reported with a carrier frequency of 0.00000 in 7636 unselected prostate cancer patients and 0.00008 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Apr 11, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jan 02, 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.6121A>G (p.Met2041Val) results in a conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6121A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36243179). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

not provided Uncertain:1

Jan 22, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30287823)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.94	L
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.47		Gain of ubiquitination at K2044 (P = 0.1093)
MVP		0.86
MPC		0.13
ClinPred		0.068	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.35
Mutation Taster		=85/15	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: rs759753186; hg19: chr11-108186763;