rs757172522

Variant names:

• chr11-108289018-A-C
• rs757172522
• NM_000051.4:c.4151A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108289018-A-C
• chr11-108289018-A-G
• chr11-108289018-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000051.4(ATM):​c.4151A>C​(p.His1384Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,278 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. H1384Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.56
• Publications: 2 publications found

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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33135992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.4151A>C	p.His1384Pro	missense	Exon 28 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4151A>C	p.His1384Pro	missense	Exon 29 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.4151A>C	p.His1384Pro	missense	Exon 28 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.4151A>C	p.His1384Pro	missense	Exon 29 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.4151A>C	p.His1384Pro	missense	Exon 28 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726986

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111664

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 11, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.4151A>C at the cDNA level, p.His1384Pro (H1384P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM His1384Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM His1384Pro occurs at a position that is conserved in mammals and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM His1384Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Mar 09, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:2

Nov 18, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting c.4151A>C located in exon 28 of the ATM gene, is predicted to result in the substitution of histidine by proline at codon 1384, p.(His1384Pro). It is not present in the population database gnomAD v2.1.1 (non-cancer, exome only subset) (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.256) is indeterminate regarding the effect that it may have on protein function. To our knowledge, functional studies have not been reported for this variant. In addition, the variant was also identified in the ClinVar database (4x uncertain significance) but is not present in LOVD database. Based on currently available information, the variant c.4151A>C is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version v1.1.

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1384P variant (also known as c.4151A>C), located in coding exon 27 of the ATM gene, results from an A to C substitution at nucleotide position 4151. The histidine at codon 1384 is replaced by proline, an amino acid with similar properties. This alteration has been reported in an individual with chronic lymphocytic leukemia (Nadeu F et al. Blood, 2016 04;127:2122-30). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Ataxia-telangiectasia syndrome Uncertain:1

Mar 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1384 of the ATM protein (p.His1384Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic lymphocytic leukemia (CLL) (PMID: 26837699). ClinVar contains an entry for this variant (Variation ID: 421181). 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. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.022	D
Polyphen		0.56	P
Vest4		0.53
MutPred		0.30		Gain of disorder (P = 0.0387)
MVP		0.86
MPC		0.28
ClinPred		0.87	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.69
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs757172522; hg19: chr11-108159745;