rs34640941

Variant names:

• chr11-108289789-A-G
• rs34640941
• NM_000051.4:c.4424A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108289789-A-G
• chr11-108289789-A-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000051.4(ATM):​c.4424A>G​(p.Tyr1475Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000974 in 1,612,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. Y1475D) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:17
• Conservation: PhyloP100: 3.91
• Publications: 26 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

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 39 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.07898763).
• BP6: Variant 11-108289789-A-G is Benign according to our data. Variant chr11-108289789-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127392.

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.4424A>G	p.Tyr1475Cys	missense	Exon 29 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4424A>G	p.Tyr1475Cys	missense	Exon 30 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.4424A>G	p.Tyr1475Cys	missense	Exon 29 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.4424A>G	p.Tyr1475Cys	missense	Exon 30 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.4424A>G	p.Tyr1475Cys	missense	Exon 29 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000600 AC: 150 AN: 250206 AF XY: 0.000577

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000946

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1460346 Hom.: 0 Cov.: 31 AF XY: 0.000953 AC XY: 692 AN XY: 726494

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.000313 AC: 14 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.000956 AC: 51 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5140

European-Non Finnish (NFE) AF: 0.00124 AC: 1374 AN: 1111566

Other (OTH) AF: 0.000813 AC: 49 AN: 60296

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000945 Hom.: 0

Bravo AF: 0.000518

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00125

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	Ataxia-telangiectasia syndrome (7)
-	1	4	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	1	3	not specified (4)
-	1	1	Familial cancer of breast (2)
-	1	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	-	1	ATM-related disorder (1)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	M
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Benign	0.085	T
Sift4G	Benign	0.090	T
Polyphen		0.87	P
Vest4		0.35
MVP		0.91
MPC		0.16
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.34
gMVP		0.51
Mutation Taster		=55/45	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: rs34640941; hg19: chr11-108160516; COSMIC: COSV53763152;