rs1555110591

Positions:

• chr11-108310315-G-A
• chr11-108310315-G-C
• chr11-108310315-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.5918G>A​(p.Arg1973Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 4.77

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATM (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5918G>A	p.Arg1973Lys	missense_variant, splice_region_variant	39/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5918G>A	p.Arg1973Lys	missense_variant, splice_region_variant	39/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460208 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2023	The c.5918G>A variant (also known as p.R1973K), located in coding exon 38 of the ATM gene, results from a G to A substitution at nucleotide position 5918. This variant was reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). The amino acid change results in arginine to lysine at codon 1973, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 38, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 03, 2023	This synonymous variant alters the conserved c.G at the last nucleotide of exon 39 of the ATM gene. Splice site prediction tools suggest that this variant may impact RNA splicing. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000665599.4). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). 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. -

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1973 of the ATM protein (p.Arg1973Lys). This variant also falls at the last nucleotide of exon 39, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 481292). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (Invitae). 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	0.012
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.60	T;.
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.17
Sift	Benign	0.087	T;T
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0060	B;B
Vest4		0.49
MutPred		0.36		Gain of ubiquitination at R1973 (P = 0.0014);Gain of ubiquitination at R1973 (P = 0.0014);
MVP		0.95
MPC		0.16
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.29
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555110591; hg19: chr11-108181042;