rs142358238

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-108229312-G-A
• chr11-108229312-G-T
• chr11-108229312-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000051.4(ATM):​c.320G>A​(p.Cys107Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,612,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:10
• Conservation: PhyloP100: 3.98
• Publications: 11 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

Y_RNA (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018790364).
• BP6: Variant 11-108229312-G-A is Benign according to our data. Variant chr11-108229312-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127368.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000773 (113/1460926) while in subpopulation AFR AF = 0.00242 (81/33456). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAdExome4. There are 44 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.320G>A	p.Cys107Tyr	missense	Exon 4 of 63	NP_000042.3
	ATM	NM_001351834.2		c.320G>A	p.Cys107Tyr	missense	Exon 5 of 64	NP_001338763.1	Q13315
	ATM	NM_001351835.2		c.320G>A	p.Cys107Tyr	missense	Exon 4 of 4	NP_001338764.1	Q6P7P1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.320G>A	p.Cys107Tyr	missense	Exon 4 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.320G>A	p.Cys107Tyr	missense	Exon 5 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.320G>A	p.Cys107Tyr	missense	Exon 4 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.000561 AC: 85 AN: 151400 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000164 AC: 41 AN: 250714 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1460926 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 726764

African (AFR) AF: 0.00242 AC: 81 AN: 33456

American (AMR) AF: 0.000224 AC: 10 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111454

Other (OTH) AF: 0.000232 AC: 14 AN: 60326

GnomAD4 genome AF: 0.000555 AC: 84 AN: 151468 Hom.: 0 Cov.: 33 AF XY: 0.000528 AC XY: 39 AN XY: 73930

African (AFR) AF: 0.00189 AC: 78 AN: 41350

American (AMR) AF: 0.000197 AC: 3 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67920

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000684

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	2	2	Hereditary cancer-predisposing syndrome (4)
-	1	2	Ataxia-telangiectasia syndrome (3)
-	-	2	not specified (2)
-	1	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	1	-	ATM-related disorder (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.29
Sift	Benign	0.092	T
Sift4G	Uncertain	0.026	D
Polyphen		0.0020	B
Vest4		0.55
MVP		0.85
MPC		0.28
ClinPred		0.059	T
GERP RS		4.9
Varity_R		0.41
gMVP		0.45
Mutation Taster		=12/88	disease causing

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: rs142358238; hg19: chr11-108100039;