rs121434216

Variant names:

• chr11-108345804-T-G
• rs121434216
• NM_000051.4:c.8480T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM3_Strong PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.8480T>G variant in ATM is a missense variant predicted to cause the substitution of phenylalanine by cysteine at amino acid 2827 (p.Phe2827Cys). This variant has been detected in at least one individual with Ataxia-Telangiectasia, who was described having a mild presentation (PMIDs: 8755918, 9000145, 9463314, 15928302, 19431188, 25040471, 30549301). The highest population minor allele frequency in gnomAD v4.1 is 0.00002196 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). Stable transfection of ATM-based cDNA constructs in an ATM-null lymphoblastoid cell line showed slightly decreased levels of kinase activity (caused by protein instability) indicating that this variant impacts protein function (PMID 19431188). The computational predictor, REVEL, gives a score of 0.889, which is above the threshold of 0.7333, evidence that correlates with impact on ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PS3_Supporting, PM3_Strong, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA115928/MONDO:0700270/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 8.00
• 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]

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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8480T>G	p.Phe2827Cys	missense_variant	Exon 58 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8480T>G	p.Phe2827Cys	missense_variant	Exon 58 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461578 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATM function (PMID: 9000145, 19431188, 25040471). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3022). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 8755918, 30549301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2827 of the ATM protein (p.Phe2827Cys). -

Jan 30, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8480T>G (p.Phe2827Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. c.8480T>G has been reported in the literature in at least one individual affected with Ataxia-Telangiectasia and cited by several others (McConville_1996 cited in Jackson_2016, Schon_2019, Thompson_2005, Stankovic_1998). Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced stability (example, Barone_2009, Taylor_2015). The following publications have been ascertained in the context of this evaluation (PMID: 35710434, 19431188, 26896183, 8755918, 30549301, 9463314, 15928302). ClinVar contains an entry for this variant (Variation ID: 3022). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

ATM-related cancer predisposition Pathogenic:1

Jun 19, 2025

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.8480T>G variant in ATM is a missense variant predicted to cause the substitution of phenylalanine by cysteine at amino acid 2827 (p.Phe2827Cys). This variant has been detected in at least one individual with Ataxia-Telangiectasia, who was described having a mild presentation (PMIDs: 8755918, 9000145, 9463314, 15928302, 19431188, 25040471, 30549301). The highest population minor allele frequency in gnomAD v4.1 is 0.00002196 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). Stable transfection of ATM-based cDNA constructs in an ATM-null lymphoblastoid cell line showed slightly decreased levels of kinase activity (caused by protein instability) indicating that this variant impacts protein function (PMID 19431188). The computational predictor, REVEL, gives a score of 0.889, which is above the threshold of 0.7333, evidence that correlates with impact on ATM function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PS3_Supporting, PM3_Strong, PP3) -

Ataxia - telangiectasia variant Pathogenic:1

Aug 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 05, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in an individual with early-onset breast cancer (Akbar et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22529920, 23532176, 8789452, 27304073, 11826028, 15279807, 30665703, 17855419, 35710434, 25040471, 26896183, 30549301, 8755918, 19431188, 9000145) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 09, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with cysteine at codon 2827 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes ATM protein to be unstable, resulting in a reduced kinase activity and DNA damage response (PMID: 19431188, 25040471). This variant has been observed in an individual affected with breast cancer (Color internal data). This variant has been reported in at least two individuals affected with mild form of autosomal recessive ataxia-telangiectasia in compound heterozygous state with a pathogenic truncation variant (PMID: 8755918, 9000145, 9463314, 15928302, 25040471, 30549301), indicating that this variant contributes to disease and appears to be hypomorphic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. Medical management should be considered based on the individual’s personal and family history. -

Familial cancer of breast Pathogenic:1

Dec 14, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		8.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.92		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		1.0
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.82
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs121434216; hg19: chr11-108216531; COSMIC: COSV53741029;