chr11-108249096-T-C

Variant names:

• chr11-108249096-T-C
• rs56128736
• NM_000051.4:c.1229T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.1229T>C​(p.Val410Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,613,936 control chromosomes in the GnomAD database, including 11 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. V410M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:27 O:1
• Conservation: PhyloP100: 7.12
• Publications: 74 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 32 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.012444019).
• BP6: Variant 11-108249096-T-C is Benign according to our data. Variant chr11-108249096-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127332.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00185 (281/152280) while in subpopulation AMR AF = 0.00392 (60/15290). AF 95% confidence interval is 0.00313. There are 2 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1229T>C	p.Val410Ala	missense	Exon 9 of 63	NP_000042.3
	ATM	NM_001351834.2		c.1229T>C	p.Val410Ala	missense	Exon 10 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.1229T>C	p.Val410Ala	missense	Exon 9 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.1229T>C	p.Val410Ala	missense	Exon 10 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.1229T>C	p.Val410Ala	missense	Exon 9 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00222 AC: 558 AN: 251102 AF XY: 0.00229

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00292 AC: 4273 AN: 1461656 Hom.: 9 Cov.: 33 AF XY: 0.00278 AC XY: 2021 AN XY: 727132

African (AFR) AF: 0.000836 AC: 28 AN: 33476

American (AMR) AF: 0.00304 AC: 136 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53368

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.00346 AC: 3844 AN: 1111918

Other (OTH) AF: 0.00290 AC: 175 AN: 60384

GnomAD4 genome AF: 0.00185 AC: 281 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74452

African (AFR) AF: 0.000601 AC: 25 AN: 41570

American (AMR) AF: 0.00392 AC: 60 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00275 AC: 187 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00300 Hom.: 9

Bravo AF: 0.00230

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00216 AC: 262

EpiCase AF: 0.00278

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	6	not provided (8)
-	-	6	Ataxia-telangiectasia syndrome (6)
-	1	5	Hereditary cancer-predisposing syndrome (6)
-	-	5	not specified (6)
-	-	1	ATM-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.43	B
Vest4		0.42
MVP		0.99
MPC		0.23
ClinPred		0.065	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.48
Mutation Taster		=93/7	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: rs56128736; hg19: chr11-108119823; COSMIC: COSV53726818; COSMIC: COSV53726818;