rs641252

chr11-108257592-A-Cchr11-108257592-A-Gchr11-108257592-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):c.2362A>C(p.Ser788Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,613,806 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S788N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (5 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 2.73

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061477125).
• BP6: Variant 11-108257592-A-C is Benign according to our data. Variant chr11-108257592-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 127349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00242 (368/152330) while in subpopulation AFR AF= 0.00844 (351/41574). AF 95% confidence interval is 0.00771. There are 0 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2362A>C	p.Ser788Arg	missense_variant	15/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2362A>C	p.Ser788Arg	missense_variant	15/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251232 Hom.: 2 AF XY: 0.000567 AC XY: 77 AN XY: 135808

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000260

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: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000280 AC: 409 AN: 1461476 Hom.: 5 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 727050

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000335

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: 0.00000450

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74480

Gnomad4 AFR AF: 0.00844

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000535 Hom.: 1

Bravo AF: 0.00306

ESP6500AA AF: 0.00750 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:6

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 30, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.2362A>C p.(Ser788Arg) missense variant has an allele frequency of 0.00944 (0.94%, 223/23,614 alleles) in the African population of the gnomAD v2.1.1 non-cancer dataset. Therefore, this variant meets a stand-alone criterion to be classified as benign (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026). -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 26, 2017	- -

Ataxia-telangiectasia syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 16, 2017	- -

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2015	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Apr 25, 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.Ser788Arg variant was identified in 3 of 3974 proband chromosomes (frequency: 0.00075) from individuals or families with Lynch Syndrome, breast cancer and a general healthy ancestrally diverse cohort in a study of germline variation in cancer-susceptibility genes (Bodian 2014, Yurgelun 2015, Ianuzzi 2002). The variant was also identified in dbSNP (ID: rs641252) as “With other allele” and ClinVar (4x as benign by Invitae, EGL Genetics, Color, GeneDx and 6x as likely benign by University of Chicago Genetic services, Institute for Biomarker, Counsyl, True Health Diagnostics) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB or LOVD 3.0, databases. The variant was identified in control databases in 242 of 276996 chromosomes (2 homozygous) at a frequency of 0.00087 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 230 of 24034 chromosomes (freq: 0.0095), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 8 of 34420 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 126668 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser788Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Benign	0.84
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T;T;.
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.068	.;B;B
Vest4		0.52, 0.75
MutPred		0.45		Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP		0.72
MPC		0.14
ClinPred		0.0016	T
GERP RS		3.8
Varity_R		0.062
gMVP		0.17

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: rs641252; hg19: chr11-108128319;