rs139552233

Positions:

• chr11-108271261-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.2932T>C​(p.Ser978Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000806 in 1,613,970 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S978Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (7 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:19
• Conservation: PhyloP100: 6.40

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03129506).
• BP6: Variant 11-108271261-T-C is Benign according to our data. Variant chr11-108271261-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=9, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00044 (67/152256) while in subpopulation SAS AF= 0.00352 (17/4830). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2932T>C	p.Ser978Pro	missense_variant	20/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2932T>C	p.Ser978Pro	missense_variant	20/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000951 AC: 239 AN: 251278 Hom.: 2 AF XY: 0.00124 AC XY: 169 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000844 AC: 1234 AN: 1461714 Hom.: 7 Cov.: 36 AF XY: 0.000945 AC XY: 687 AN XY: 727166

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00495

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000638

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00124 AC: 151

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ATM: BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 29, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ataxia-telangiectasia syndrome Uncertain:2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 09, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -

not specified Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2021	Variant summary: ATM c.2932T>C (p.Ser978Pro) results in a non-conservative amino acid change in 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 0.00092 in 266408 control chromosomes, predominantly at a frequency of 0.0049 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Furthermore, it has also been reported among five individuals who are cancer free at age 70 in the FLOSSIES database. This variant has been reported in multiple affected individuals with classical AT, classical Hodgkins lymphoma, B-NHL, BrC, CRC etc. Among them the one patient with classical AT also carried another ATM variant c.8395-8404del10, and no residual ATM activity was detected via western blot in this patient sample and only about 10% expressed ATM protein detected compared to WT (Carney_2012). However, the possibility of an undetected second variant causing AT in this patient cannot be ruled out. A study evaluating the Rate Ratio of asynchronous contralateral breast cancer associated with ATM gene mutation carrier status found a non-statistically significant risk of contralateral breast cancer for missense variants in the ATM gene (RR 1.2, 95% CI = 0.8 to 1.7) (Bernstein_2010). This low RR and a 95% CI overlapping 1.0 indicate very little confidence in the assertion of association with breast cancer. Subsequently, this variant has been reported in cases and in controls by other studies (example, Dorling_2021). Multiple ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4), likely benign (n=4) and benign (n=5). Based on the evidence outlined above, and the emerging peer consensus, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 19, 2017	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 01, 2021	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 05, 2023

- -

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.Ser978Pro variant was identified in 10 of 9598 proband chromosomes (frequency: 0.001) from individuals or families with HBOC, Hereditary Diffuse Gastric Cancer (HDGC), Non-Hodgkin’s lymphoma, Ataxia Telangiectasia (AT), or high risk cancer, and was not identified in 168 control chromosomes from healthy individuals (Yurgelun 2015, Caminsky 2016, Castera 2014, Hansford 2015, Maxwell 2016, Bernstein 2010, Gumy Pause 2006, Carney 2012). The variant co-occurred with an ATM variant (c.8395_8404del) in an AT patient whose residual ATM protein expression level was found to be 10% (Carney 2012). The variant was also identified in dbSNP (ID: rs139552233) “With other allele” and ClinVar (classified as benign by GeneDx, Invitae and Ambry Genetics; as likely benign by EGL Genetic Diagnostics and Counsyl; and as uncertain significance by Praxis fuer Humangentik Tuebingen and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 248 of 277020 chromosomes (2 homozygous) at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 154 (2 homozygous) of 30778 chromosomes (freq: 0.005), Other in 6 of 6456 chromosomes (freq: 0.0009), Latino in 4 of 34408 chromosomes (freq: 0.0001), and European Non-Finnish in 84 of 126608 chromosomes (freq: 0.0007), while it was not observed in the African, Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser978Pro is located in the ß-adaptin binding domain and the p.Ser978 residue is conserved across mammals and other organisms; 5 of 5 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 only 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 10, 2024

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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	0.65
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.94, 0.94
MVP		0.95
MPC		0.52
ClinPred		0.12	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.61

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: rs139552233; hg19: chr11-108141988; COSMIC: COSV53765841;