rs768461085

chr11-108330288-G-Achr11-108330288-G-Cchr11-108330288-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000051.4(ATM):c.7382G>A(p.Arg2461His) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2461C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 6.34

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000051.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7382G>A	p.Arg2461His	missense_variant	50/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7382G>A	p.Arg2461His	missense_variant	50/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251270 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 20, 2017	In the published literature, the variant has been reported in individuals with breast/ovarian cancer (PMIDs: 34570441 (2021), 34299313 (2021)), 30982232 (2019), 30287823 (2018), 28779002 (2017)), in an individual with prostate cancer (PMD: 31214711 (2020)), as well as in a healthy control (PMID: 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25742471, 28779002, 28949453, 23532176, 30287823, 35186721, 34570441, 34299313, 33471991, 29684080, 31214711) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2461 of the ATM protein (p.Arg2461His). This variant is present in population databases (rs768461085, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 30287823, 30982232, 31214711). ClinVar contains an entry for this variant (Variation ID: 216230). 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. 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. -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in ATM is predicted to replace arginine with histidine at codon 2461, p.(Arg2461His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the FAT domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (8/34,588 alleles) in the Latino/admixed American population. The prevalence of the variant in affected individuals with breast cancer and prostate cancer is not significantly increased compared with the prevalence in controls (PMID: 30287823, 30982232, 31214711, 33471991). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 13, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2022	This missense variant replaces arginine with histidine at codon 2461 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with breast and prostate cancer (PMID: 30287823, 30982232, 31214711, 33471991, 34299313), but also in an unaffected controls (PMID: 30287823, 33471991). This variant has been identified in 10/251270 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2023	The p.R2461H variant (also known as c.7382G>A), located in coding exon 49 of the ATM gene, results from a G to A substitution at nucleotide position 7382. The arginine at codon 2461 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in cancer cohorts as well as control groups across multiple studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083;Yehia L et al. PLoS Genet, 2018 04;14:e1007352; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376). This amino acid position is well 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 08, 2022

Variant summary: ATM c.7382G>A (p.Arg2461His) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 273752 control chromosomes (gnomAD, Momozawa_2018). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (4e-05 vs 0.001), allowing no conclusion about variant significance. c.7382G>A has been reported in the literature in individuals affected with Breast and Prostate Cancer (example: Momozawa_2018, Wang_2019, Momozawa_2020, Guglielmi_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.093	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.36
MutPred		0.50		Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);
MVP		0.96
MPC		0.26
ClinPred		0.40	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.35

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: rs768461085; hg19: chr11-108201015; COSMIC: COSV99590879; COSMIC: COSV99590879;