chr11-108249096-T-C

Variant names:

• chr11-108249096-T-C
• rs56128736
• NM_000051.4:c.1229T>C
• ATM p.Val410Ala

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BS2BP4BP6_Strong

The NM_000051.4(ATM):c.1229T>C (p.Val410Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00282 (AC=4,554) in the gnomAD database across 1,613,936 control chromosomes, including 11 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00337. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V410L: Uncertain_significance (ClinVar VariationId 3967210, 1 star); p.V410M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 216190); p.V410= (synonymous): Likely_benign (ClinVar VariationId 453357, 2 stars); p.V410= (synonymous): Likely_benign (ClinVar VariationId 1155205, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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:2 B:28 O:1
• Conservation: PhyloP100: 7.12
• Publications: 22 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: Natera, Ambry Genetics
• ataxia telangiectasia

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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (22/24 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 11.; Very high cumulative gnomAD AC = 4554 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated classification 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	Prot: NP_000042.3
	ATM NM_001351834.2		c.1229T>C p.Val410Ala	missense	Exon 10 of 64	Prot: NP_001338763.1 UniProt:

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.1229T>Cp.Val410Ala

Exon rankExon 9 of 63

missense

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.1229T>Cp.Val410Ala

Exon rankExon 10 of 64

missense

Prot: NP_001338763.1UniProt: 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	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.1229T>C p.Val410Ala	missense	Exon 10 of 64	Prot: ENSP00000388058.2 UniProt:
	ATM ENST00000531525.3	TSL:1	c.1229T>C p.Val410Ala	missense	Exon 9 of 30	Prot: ENSP00000434327.3 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.1229T>Cp.Val410Ala

Exon rankExon 9 of 63

missense

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.1229T>Cp.Val410Ala

Exon rankExon 10 of 64

missense

Prot: ENSP00000388058.2UniProt: Q13315

ATM ENST00000531525.3

TSL:1

HGVSc / HGVSpc.1229T>Cp.Val410Ala

Exon rankExon 9 of 30

missense

Prot: ENSP00000434327.3UniProt: H0YDU7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00185	AC:281	Hom:2	AN:152162	Cov:32
GnomAD2 exomes	AF: 0.00222	AC:558	Hom:	AN:251102	Cov:
GnomAD4 exome	AF: 0.00292	AC:4273	Hom:9	AN:1461656	Cov:33
GnomAD4 genome	AF: 0.00185	AC:281	Hom:2	AN:152280	Cov:32
TOPMed (Bravo)	AF: 0.00230	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00303	AC:1109	Hom:10	AN:366086	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00683	AC:16	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00177	AC:23	Hom:	AN:12998	Cov:
Turkish Variome	AF: 0.000885	AC:4	Hom:0	AN:5176	Cov:
UK10K	AF: 0.00331	AC:25	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00189 *	21	11112	0.00272 *	48	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00362	103	28420	0.00267	77	28844
Epi25(Epilepsy)	0.00255	107	41958	0.00338	226	66888
SCHEMA(Schizophrenia)	0.00238	291	122052	0.00308	589	191192

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
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
FuncVEP CTI	Benign	0.029
GPN-Star LLR	N/A	-5.8
GPN-Star score	N/A	5.8
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	93/7	polymorphism
MutationAssessor	Uncertain	2.6	M
PhyloP100	Uncertain	7.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Varity_R	N/A	0.13
VESM-3B	Benign	-6.3

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs56128736;

hg19: chr11-108119823;

COSMIC: COSV53726818;

COSMIC: COSV53726818;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar