11-108303021-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.5488A>G(p.Met1830Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. M1830T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 0.835

Publications

8 publications found

Variant links:

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):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2012743).

BP6

Variant 11-108303021-A-G is Benign according to our data. Variant chr11-108303021-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141271.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.5488A>G	p.Met1830Val	missense_variant	Exon 36 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.5488A>G	p.Met1830Val	missense_variant	Exon 36 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250794

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1459502

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726194

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33400

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000177

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000901

AC:

AN:

1110086

Other (OTH)

AF:

0.0000166

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jul 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, but also in controls (Momozawa et al., 2018; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 27034805, 26667234, 29684080, 30287823, 32566746) -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 04, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATM-related disorder

Uncertain:1

Apr 04, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.5488A>G variant is predicted to result in the amino acid substitution p.Met1830Val. This variant has been reported with uncertain significance in individuals with breast cancer or Cowden syndome (Supplemental Data 2 in Momozawa et al. 2018. PubMed ID: 30287823; Table S9 in Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108173748-A-G), and has classifications of both uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141271). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial pancreatic carcinoma

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM p.Met1830Val variant was identified in 8 of 21,054 proband chromosomes (frequency: 0.0004) from individuals with breast and pancreatic cancer and was present in 13 of 47,462 control chromosomes (frequency: 0.0003) from healthy individuals (Momozawa 2018, Yehia 2018). The variant was identified in dbSNP (rs587781622) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, ClinVar (interpreted as "uncertain significance" by Invitae and 2 others, "likely benign" by Ambry Genetics and 1 other) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 3 of 245578 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5470 chromosomes (freq: 0.0002), European in 1 of 111,200 chromosomes (freq: 0.000009), East Asian in 1 of 17,234 chromosomes (freq: 0.00006), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Met1830 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:1

Jan 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATM c.5488A>G (p.Met1830Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250794 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5488A>G in individuals affected with Ataxia-Telangiectasia/ATM-related cancers and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.1767del , p.Pro591fs), providing supporting evidence for a benign role. ClinVar contains an entry for this variant (Variation ID: 141271). Based on the evidence outlined above, the variant was classified as likely benign. -

Ataxia-telangiectasia syndrome

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.046

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

D;.

M_CAP

Benign

0.049

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PhyloP100

0.83

PrimateAI

Benign

0.35

PROVEAN

Benign

0.46

N;N

REVEL

Benign

0.15

Sift

Benign

0.49

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0040

B;B

Vest4

0.57

MutPred

0.43

Loss of catalytic residue at M1830 (P = 0.0077);Loss of catalytic residue at M1830 (P = 0.0077);

MVP

0.72

MPC

0.13

ClinPred

0.063

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.31

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over