11-108227782-G-T

Position:

• chr11-108227782-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000051.4(ATM):​c.79G>T​(p.Val27Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V27I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.72

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17897275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.79G>T	p.Val27Phe	missense_variant	3/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.79G>T	p.Val27Phe	missense_variant	3/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 01, 2022

- -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 12, 2020

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2018

The p.V27F variant (also known as c.79G>T), located in coding exon 2 of the ATM gene, results from a G to T substitution at nucleotide position 79. The valine at codon 27 is replaced by phenylalanine, an amino acid with highly similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T;T;T;.;T;T;T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.082
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.;.;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	.;L;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.73	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D;N;D;D;.;N;.;.;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.010	D;D;D;D;D;D;.;.;.;D;D
Polyphen		0.68, 0.32	.;P;.;.;.;P;B;B;B;B;.
Vest4		0.53, 0.40, 0.34, 0.43
MutPred		0.27		Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);Loss of MoRF binding (P = 0.0825);
MVP		0.76
MPC		0.42
ClinPred		0.93	D
GERP RS		2.4
Varity_R		0.10
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs754770960; hg19: chr11-108098509;