11-108289759-T-C

Position:

• chr11-108289759-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3_Strong PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (LINK:https://erepo.genome.network/evrepo/ui/classification/CA298357/MONDO:0016419/020

• 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:6 U:1
• Conservation: PhyloP100: 7.71

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_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4394T>C	p.Leu1465Pro	missense_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4394T>C	p.Leu1465Pro	missense_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251106 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135722

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461230 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726930

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2015	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 4/4 in silico tools predict damaging outcome for this substitution. Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM variant (0.4%). The variant was reported in one A-T patient (Izatt_EJHG_1999) who was compound heterozygote for the variant of interest and a potentially deleterious frameshift/truncating variant 1355delC; p.Thr452Asnfs indicating the variant to have a role in A-T pathology. Furthermore, Izatt_EJHG_1999 showed the variant to result in low level of ATM expression indicating that the L1465P missense mutation may lead to instability of the protein. Additionally, Barone_Hum Mutat_2009 reported the L1465P ATM variant to have reduced kinase activity toward its downstream targets providing an independent support for the pathogenicity of the variant. A clinical laboratory classifies variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate) and HGMD lists variant with a classification of Disease Mutation. Considering all evidence, the variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 28, 2022	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. Experimental studies have shown that this missense change affects ATM function (PMID: 10234507, 19431188). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1465 of the ATM protein (p.Leu1465Pro). This variant is present in population databases (rs730881391, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia, esophageal cancer, gastric cancer, and/or prostate cancer (PMID: 10234507, 26681312, 26896183, 32853339, 33436325). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 181996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (</=0.001%) for PM2_Supporting, meeting this criterion. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 9463314, 10234507, 26896183). The computational predictor, Revel (Score: 0.802), predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PM2_supporting, PM3_strong, PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 12, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2023

Published functional studies demonstrate reduced kinase activity (Barone et al., 2009); Identified in individuals with breast or prostate cancer and segregates with disease in at least one family (Darst et al., 2021; Karlsson et al., 2021; Lourenco et al., 2023); 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: 27304073, 22529920, 26681312, 29308099, 29922827, 10234507, 26896183, 27153395, 33436325, 32853339, 19431188, 37232349) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The p.L1465P variant (also known as c.4394T>C), located in coding exon 28 of the ATM gene, results from a T to C substitution at nucleotide position 4394. The leucine at codon 1465 is replaced by proline, an amino acid with very few similar properties. This variant has been reported in the literature in a compound heterozygous state in an Irish individual with Ataxia-Telangiectasia (A-T). Functional analysis indicated low levels of ATM expression (1%) suggesting that this alteration likely changes the secondary structure of the protein as the proline substitution is located in the middle of a predicted α-helix from amino acids 1460 to 1476 (Izatt L et al. Eur. J. Hum. Genet. 1999 Apr; 7(3):310-20). An additional report suggests this alteration results in reduced kinase activity. Authors note that 8 of the 10 ATM variants in this study with reduced kinase activity were identified in A-T patients with a milder A-T phenotype, but do not specify which 8 (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel. This individual had a personal history of esophageal and gastric cancers (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This variant was reported in 10/5560 prostate cancer cases and in 2/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol. 2021 Aug;4:570-579). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability; however, the impact on protein function is not clear (Ambry internal data; Bareti D et al. Sci Adv. 2017 May;3(5):e1700933). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;D;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.88		Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);.;
MVP		0.98
MPC		0.73
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs730881391; hg19: chr11-108160486;