rs760471526

Positions:

• chr11-108229186-A-C
• chr11-108229186-A-G

Variant summary

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

The NM_000051.4(ATM):​c.194A>C​(p.Gln65Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.92

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 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.194A>C	p.Gln65Pro	missense_variant	4/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.194A>C	p.Gln65Pro	missense_variant	4/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2018

The p.Q65P variant (also known as c.194A>C), located in coding exon 3 of the ATM gene, results from an A to C substitution at nucleotide position 194. The glutamine at codon 65 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;T;T;.;T;T;T;T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	.;M;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;N;D;D;.;N;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.048	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.99, 0.99	.;D;.;.;.;D;D;D;D;D;.
Vest4		0.88, 0.87, 0.92, 0.82
MutPred		0.35		Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);Loss of MoRF binding (P = 0.048);
MVP		0.91
MPC		0.62
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760471526; hg19: chr11-108099913; COSMIC: COSV53725961; COSMIC: COSV53725961;