rs138327406

Positions:

• chr11-108289753-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_000051.4(ATM):​c.4388T>G​(p.Phe1463Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000897 in 1,613,668 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (11 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:18 O: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 Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.012310088).
• BP6: Variant 11-108289753-T-G is Benign according to our data. Variant chr11-108289753-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127388.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, not_provided=1, Benign=8, Uncertain_significance=3}. Variant chr11-108289753-T-G is described in Lovd as [Benign]. Variant chr11-108289753-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4388T>G	p.Phe1463Cys	missense_variant	29/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4388T>G	p.Phe1463Cys	missense_variant	29/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251198 Hom.: 6 AF XY: 0.00156 AC XY: 212 AN XY: 135762

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.000881 AC: 1288 AN: 1461324 Hom.: 11 Cov.: 31 AF XY: 0.000923 AC XY: 671 AN XY: 726968

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74494

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00191 Hom.: 7

Bravo AF: 0.00125

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:18 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 30, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 26, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 04, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 26, 2015	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2016	Variant summary: The ATM c.4388T>G (p.Phe1463Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated by any in vitro/vivo functional studies. This variant was found in 172/120622 control chromosomes (3 homozygotes) at a frequency of 0.0014259, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic ATM variant for breast cancer (0.0005001), suggesting this variant does not cause breast cancer. The variant was found in 149/65460 European non-Finnish chromosomes (0.002276) with 3 homozygotes; while this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant for Ataxia-telangiectasia (AT; 0.0039528), AT is a childhood disorder, and thus it would be unlikely for there to be 3 homozygous unaffected individuals in the ExAC database. Furthermore, it has been shown that while heterozygotes are not at increased risk of developing A-T neurologic manifestations, they have a fourfold increased risk of developing breast cancer through mechanisms that are not understood. Thus, if this were a pathogenic AT-causing variant, it would increase the risk of breast cancer. However, population control data strongly indicate that this variant does not cause breast cancer.This variant has been reported in patients with a variety types of cancers such as BrC, HD, HBOC, B-CLL, OvC, Pancreatic Cancer, and hemangioblastomas, however, there was no strong evidence to support the causative correlation of this variant with the diseases. Additionally, the variant was found to co-occur with likely pathogenic variants (BRIP1 c.440dupA and ATM c.1027_1030delGAAA) in internal specimens tested for cancer risk.Two clinical laboratories (via ClinVar) classified this variant as benign, one classified this variant as likely benign, and two labs classified it as VUS, without evidence to independently evaluate. Considering all, the variant was classified as Likely Benign until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATM: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Phe1463Cys variant was identified in 12 of 4036 proband chromosomes (frequency: 0.00297) from individuals or families with breast cancer, ovarian cancer, Non-Hodgkin's lymphoma and Lynch syndrome (Liberzon 2004, Maillet 2002, Stafford 2017, Tung 2016, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSBP (ID: rs138327406) as “With other allele”, ClinVar 6x with conflicting interpretations of pathogenicity (as uncertain significance by EGL Genetic and Vantari Genetics, as likely benign by GeneDx, and as benign by Invitae and Ambry Genetics), Clinvitae (4x), and Cosmic databases. The variant was not identified in MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 405 of 276966 chromosomes at a frequency of 0.001462 in the following populations: Ashkenazi Jewish in 274 (7 homozygous) of 10144 chromosomes (freq. 0.027), Other in 21 of 6456 chromosomes (freq. 0.0033), Latino in 35 of 34392 chromosomes (freq. 0.001), European (Non-Finnish) in 67 of 126564 chromosomes (freq. 0.0005) and African in 8 of 24014 (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Phe1463Cys variant was found to co-occur with p.Pro604Ser in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). One study concluded that the p.Phe1463Cys variant is pathogenic in breast cancer because the amino acid substitution is known to be deleterious to ATM function in patients with B cell non-Hodgkin’s lymphomas, as well as based on conservation data (Maillet 2002). The p.Phe1463 residue is conserved in mammals but not in more distantly related organisms, and 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 variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 17, 2024

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;D;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.2	D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MVP		0.94
MPC		0.69
ClinPred		0.053	T
GERP RS		5.6
Varity_R		0.72
gMVP		0.70

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: rs138327406; hg19: chr11-108160480; COSMIC: COSV53781383; COSMIC: COSV53781383;