rs786202270

Positions:

• chr11-108257506-G-A
• chr11-108257506-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000051.4(ATM):​c.2276G>A​(p.Ser759Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S759G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (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:7
• Conservation: PhyloP100: 3.85

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30286187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2276G>A	p.Ser759Asn	missense_variant	15/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2276G>A	p.Ser759Asn	missense_variant	15/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461246 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726934

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000332 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 09, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 759 of the ATM protein (p.Ser759Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19781682, 29470806). ClinVar contains an entry for this variant (Variation ID: 185556). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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, criteria provided, single submitter	clinical testing	Counsyl	Jun 19, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces serine with asparagine at codon 759 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 19781682). This variant has not been identified 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2023	The p.S759N variant (also known as c.2276G>A), located in coding exon 14 of the ATM gene, results from a G to A substitution at nucleotide position 2276. The serine at codon 759 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). Additionally, this alteration was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). This amino acid position is 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer without detailed clinical information provided (Tavtigian et al., 2009; Broeks et al., 2008); This variant is associated with the following publications: (PMID: 17393301, 29470806, 19781682) -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	.;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	.;M;M
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T;T
Sift4G	Uncertain	0.040	D;T;T
Polyphen		0.96	.;D;D
Vest4		0.53, 0.47
MVP		0.86
MPC		0.29
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
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: rs786202270; hg19: chr11-108128233;