rs1060504312

Variant names:

• chr11-108243960-C-G
• rs1060504312
• NM_000051.4:c.504C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108243960-C-G
• chr11-108243960-C-T
• chr11-108243960-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000051.4(ATM):​c.504C>G​(p.Phe168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 143,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F168Y) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 31)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.806
• Publications: 4 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):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

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

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

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

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 47 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05384499).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.504C>G	p.Phe168Leu	missense	Exon 6 of 63	NP_000042.3
	ATM	NM_001351834.2		c.504C>G	p.Phe168Leu	missense	Exon 7 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.504C>G	p.Phe168Leu	missense	Exon 6 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.504C>G	p.Phe168Leu	missense	Exon 7 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.504C>G	p.Phe168Leu	missense	Exon 6 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.0000140 AC: 2 AN: 143092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000140 AC: 2 AN: 143092 Hom.: 0 Cov.: 31 AF XY: 0.0000144 AC XY: 1 AN XY: 69218

African (AFR) AF: 0.0000518 AC: 2 AN: 38610

American (AMR) AF: 0.00 AC: 0 AN: 14342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00 AC: 0 AN: 4596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65722

Other (OTH) AF: 0.00 AC: 0 AN: 1976

Alfa AF: 0.0000204 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Ataxia-telangiectasia syndrome (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.5
DANN	Benign	0.80
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.23	N
PhyloP100		0.81
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.26		Loss of stability (P = 0.2436)
MVP		0.78
MPC		0.14
ClinPred		0.090	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.17
Mutation Taster		=99/1	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: rs1060504312; hg19: chr11-108114687;