chr11-108317374-C-A

Position:

• chr11-108317374-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.6200C>A​(p.Ala2067Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000343 in 1,458,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.9901
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 3.60

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]

ATM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 11-108317374-C-A is Pathogenic according to our data. Variant chr11-108317374-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.6200C>A	p.Ala2067Asp	missense_variant, splice_region_variant	43/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6200C>A	p.Ala2067Asp	missense_variant, splice_region_variant	43/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251316 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000343 AC: 5 AN: 1458878 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2067 of the ATM protein (p.Ala2067Asp). This variant is present in population databases (rs397514577, gnomAD 0.0009%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 9887333, 22345219, 25914063; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39749). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 25077176). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 23, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 04, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 29, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19650357, 22345219, 25077176]. Functional studies indicate this variant impacts protein function [PMID: 19650357, 25077176]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2023	The p.A2067D pathogenic mutation (also known as c.6200C>A), located in coding exon 42 of the ATM gene, results from a C to A substitution at nucleotide position 6200. The alanine at codon 2067 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in two individuals/families with ataxia-telangiectasia (Sandoval N et a. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Dawson AJ et al. Am. J. Med. Genet. 2015 Aug;167A(8):1937-9). This alteration has also been shown to segregate with primary-appearing dystonia in homozygous individuals from three Canadian Mennonite families (Saunders-Pullman R et al. Neurology. 2012 Feb; 78(9):649-57). Additionally, functional assays demonstrated that this alteration results in reduced protein expression, absent autophosphorylation, and diminished transphorphylation of downstream ATM targets (Nakamura K et al. Mol Genet Genomic Med. 2014 Jul; 2(4):332-40). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, this variant is unlikely to be causative of classical ataxia-telangiectasia; however, it may be associated with dystonia and may lead to increased risk of developing ATM-related cancer. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2022	This missense variant replaces alanine with aspartic acid at codon 2067 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). This variant has been reported in multiple individuals affected with breast cancer (PMID: 20305132, 26898890; Color internal data) and pancreatic cancer (Color internal data). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with typical or mild ataxia telangiectasia (PMID: 9887333, 22345219, 25037873, 25077176, 25914063). Lymphoblastoid cells isolated from the homozygous carriers have shown absent to trace levels of ATM protein, reduced ATM kinase activity, and increased sensitivity to radiation, indicating reduced capacity to repair DNA damage (PMID: 22345219, 25077176). This variant has been identified in 1/251316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 19, 2023

- -

Ataxia - telangiectasia variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 28, 2012

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Ala2067Asp variant was identified in 64 of 23034 proband chromosomes (frequency: 0.003) from individuals or families with atypical or “variant-Ataxia Telangiectasia”, breast and ovarian cancer and was not identified in 7976 control chromosomes from healthy individuals (Sandoval 1999, Saunders-Pullman 2012, Lu 2019). The variant was identified in dbSNP (rs397514577) as “with pathogenic allele”, ClinVar (interpreted as pathogenic by Invitae and 4 others, likely pathogenic by Color and 1 other) and LOVD 3.0 (observed 11x). The variant was identified in control databases in 1 of 246,124 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111,648 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The homozygous variant was observed in 3 families with 12 affected people. Patients presented with a variant form of Ataxia Telangiectasia, a milder form of the disease, and 8 of the 12 homozygous carriers had a malignancy later in life including stomach, prostate, myeloid leukemia and lymphoma (Saunders-Pullman 2012, Nakamura 2014). Of the 10 carriers, six were homozygous and 4 were compound heterozygotes with ATM pathogenic variants (p.Arg1898*, p.Glu1978* and p.Val1268*) and segregated in trans (Nakamura 2014). Western blot of lymphoblastoid cell lines derived from these patients had decreased expression of ATM protein. Additionally, site directed mutagenesis experiments that introduced the homozygous variant had low levels of ATM protein in vitro. The presence of the variant also decreased kinase activity by ATM (Nakamura 2014). The p.Ala2067 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Ala2067Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Oct 08, 2024

According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PS3 (medium pathogenic): Nakamura 2014 (PMID: 25077176): cell line with mutated ATM cDNA showed a trace-to-absent transphosphorylation of downstream ATM targets & ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein + Ambry Genetics (Accession: SCV000217431.8): Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). , PM2 (supporting pathogenic): V2: 0,0004%, 1 x gefunden; , PM3 (very strong pathogenic): Found in multiple cases of AT phenotype, confirmed in trans (e.g. PMID: 25077176 --> Of the 10 carriers, 6 were homozygous and 4 were compound heterozygotes with ATM pathogenic truncating variants and segregated in trans). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.88		Gain of catalytic residue at A2067 (P = 0.069);Gain of catalytic residue at A2067 (P = 0.069);
MVP		0.98
MPC		0.50
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.61
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.010		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: rs397514577; hg19: chr11-108188101; COSMIC: COSV53741904; COSMIC: COSV53741904;