NM_000051.4(ATM):c.3118A>G (p.Met1040Val) AND not specified

Germline classification:: Benign (12 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000116423.33

Allele description [Variation Report for NM_000051.4(ATM):c.3118A>G (p.Met1040Val)]

NM_000051.4(ATM):c.3118A>G (p.Met1040Val)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.3118A>G (p.Met1040Val)

Other names:

p.M1040V:ATG>GTG; NM_000051.3(ATM):c.3118A>G; NP_000042.3:p.Met1040Val

HGVS:

NC_000011.10:g.108272572A>G
NG_009830.1:g.54741A>G
NM_000051.4:c.3118A>GMANE SELECT
NM_001351834.2:c.3118A>G
NP_000042.3:p.Met1040Val
NP_000042.3:p.Met1040Val
NP_001338763.1:p.Met1040Val
LRG_135t1:c.3118A>G
LRG_135:g.54741A>G
LRG_135p1:p.Met1040Val
NC_000011.9:g.108143299A>G
NM_000051.3:c.3118A>G
Q13315:p.Met1040Val
p.M1040V

Protein change:

M1040V; MET1040VAL

Links:

UniProtKB: Q13315#VAR_010817; OMIM: 607585.0010; dbSNP: rs3092857

NCBI 1000 Genomes Browser:

rs3092857

Molecular consequence:

NM_000051.4:c.3118A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.3118A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000084268	ITMI	no classification provided	not provided	germline	reference population	PubMed (1) [See all records that cite this PMID]
SCV000150348	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Likely benign	germline	clinical testing
SCV000167077	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Nov 26, 2013)	germline	clinical testing	Citation Link,
SCV000301659	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001550824	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Benign	unknown	clinical testing
SCV001808432	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing
SCV001905781	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001923721	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001931777	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001955703	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002036771	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002760547	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
African	germline	unknown	not provided	not provided	not provided	43	not provided	reference population
African_European	germline	unknown	not provided	not provided	not provided	46	not provided	reference population
Central_Asian	germline	unknown	not provided	not provided	not provided	50	not provided	reference population
East_Asian	germline	unknown	not provided	not provided	not provided	62	not provided	reference population
European	germline	unknown	not provided	not provided	not provided	331	not provided	reference population
Hispanic	germline	unknown	not provided	not provided	not provided	118	not provided	reference population
Whole_cohort	germline	unknown	not provided	not provided	not provided	681	not provided	reference population

Citations

PubMed

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From ITMI, SCV000084268.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African	not provided	not provided	not provided	reference population	PubMed (1)
2	African_European	not provided	not provided	not provided	reference population	PubMed (1)
3	Central_Asian	not provided	not provided	not provided	reference population	PubMed (1)
4	East_Asian	not provided	not provided	not provided	reference population	PubMed (1)
5	European	not provided	not provided	not provided	reference population	PubMed (1)
6	Hispanic	not provided	not provided	not provided	reference population	PubMed (1)
7	Whole_cohort	not provided	not provided	not provided	reference population	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	43	not provided	discovery		not provided	0.0465	not provided	not provided
2	germline	unknown	46	not provided	discovery		not provided	0.0217	not provided	not provided
3	germline	unknown	50	not provided	discovery		not provided	0	not provided	not provided
4	germline	unknown	62	not provided	discovery		not provided	0	not provided	not provided
5	germline	unknown	331	not provided	discovery		not provided	0.0015	not provided	not provided
6	germline	unknown	118	not provided	discovery		not provided	0.0085	not provided	not provided
7	germline	unknown	681	not provided	discovery		not provided	0.0073	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000150348.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000167077.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000301659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The ATM p.Met1040Val variant was identified in 18 of 1214 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer or non-Hodgkin lymphoma (Thorstenson 2001, Bretsky 2003, Sipahimalani 2007). The variant was also identified in ClinVar (benign 4x: GeneDx, Ambry Genetics, Invitae, Prevention Genetics; likely benign 3x: Mercy Hospital, Illumina, University of Chicago; not provided 1x: ITMI) unconfirmed somatic 1x: OMIM), COSMIC (2 lymphoid neoplasms, somatic status unknown), MutDB (link to UniProtKB/Swiss-Prot database, variant is unclassified with poor conservation across species), databases. The variant was not identified in the GeneInsight-COGR, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1095 (27 homozygous) of 277102 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1012 of 24020 chromosomes (freq: 0.042). The p.Met1040Val residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, and HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808432.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001905781.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955703.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036771.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002760547.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

Relating variation to medicine