chr11-108229312-G-T

Variant names:

• chr11-108229312-G-T
• rs142358238
• NM_000051.4:c.320G>T

Variant summary

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

The NM_000051.4(ATM):​c.320G>T​(p.Cys107Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,926 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C107R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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]

Y_RNA (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 rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.320G>T	p.Cys107Phe	missense_variant	Exon 4 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.320G>T	p.Cys107Phe	missense_variant	Exon 4 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460926 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726764

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C107F variant (also known as c.320G>T), located in coding exon 3 of the ATM gene, results from a G to T substitution at nucleotide position 320. The cysteine at codon 107 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well 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	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.054	.;T;T;.;T;T;T;T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;.;.;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	.;M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;N;D;.;N;.;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.11	T;T;D;.;T;.;.;.;.;.
Sift4G	Uncertain	0.038	D;D;T;T;D;.;.;.;T;T
Polyphen		0.0050, 0.88	.;B;.;.;B;P;P;P;P;.
Vest4		0.76, 0.77, 0.80, 0.72
MutPred		0.64		Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);Loss of catalytic residue at I105 (P = 0.1057);
MVP		0.93
MPC		0.64
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.47
gMVP		0.39

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: rs142358238; hg19: chr11-108100039;