rs587779820

chr11-108257563-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.2333A>G(p.Asn778Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N778D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: -0.259

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07723367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2333A>G	p.Asn778Ser	missense_variant	15/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2333A>G	p.Asn778Ser	missense_variant	15/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727168

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The ATM c.2333A>G (p.Asn778Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the Armadillo-type fold domain (IPR016024) (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 1/121360 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. This variant was reported in patients with breast, ovarian, and pancreatic cancer without strong evidence for causality (Bernstein_2010, Grant_2015, Lu_2015, Tung_2015). The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. This variant is classified as a variant of uncertain significance (VUS) until more clinical and functional studies become available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast, ovarian, or pancreatic cancer (Bernstein 2010, Grant 2015, Lu 2015, Tung 2015); This variant is associated with the following publications: (PMID: 25479140, 26689913, 20305132, 25186627) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ATM: PM2, BP4 -

Ataxia-telangiectasia syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 778 of the ATM protein (p.Asn778Ser). This variant is present in population databases (rs587779820, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 20305132, 25186627, 25479140, 26689913). ClinVar contains an entry for this variant (Variation ID: 127348). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 05, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2023	The p.N778S variant (also known as c.2333A>G), located in coding exon 14 of the ATM gene, results from an A to G substitution at nucleotide position 2333. The asparagine at codon 778 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in several cohorts of breast cancer patients (Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Tung N et al. Cancer, 2015 Jan;121:25-33; Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in 1/290 individuals with pancreatic cancer (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This missense variant replaces asparagine with serine at codon 778 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast, pancreatic and ovarian cancers (PMID: 20305132, 25186627, 25479140, 26689913, 29522266). This variant has been identified in 3/251370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	8.3
Dann	Benign	0.14
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.67	T;T;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.099
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.032, 0.095
MVP		0.72
MPC		0.097
ClinPred		0.031	T
GERP RS		-0.87
Varity_R		0.028
gMVP		0.073

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: rs587779820; hg19: chr11-108128290;