NM_000051.4(ATM):c.1931C>A (p.Ser644Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 23, 2021
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:: RCV000222313.6

Allele description [Variation Report for NM_000051.4(ATM):c.1931C>A (p.Ser644Ter)]

NM_000051.4(ATM):c.1931C>A (p.Ser644Ter)

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.1931C>A (p.Ser644Ter)

HGVS:

NC_000011.10:g.108253846C>A
NG_009830.1:g.36015C>A
NM_000051.4:c.1931C>AMANE SELECT
NM_001351834.2:c.1931C>A
NP_000042.3:p.Ser644Ter
NP_000042.3:p.Ser644Ter
NP_001338763.1:p.Ser644Ter
LRG_135t1:c.1931C>A
LRG_135:g.36015C>A
LRG_135p1:p.Ser644Ter
NC_000011.9:g.108124573C>A
NM_000051.3:c.1931C>A

Protein change:

S644*

Links:

dbSNP: rs768362387

NCBI 1000 Genomes Browser:

rs768362387

Molecular consequence:

NM_000051.4:c.1931C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.1931C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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SMC domain protein [Methanocaldococcus infernus ME]
SMC domain protein [Methanocaldococcus infernus ME]
gi|296109493|gnl|REF_jgi|Metin_0813 YP_003616442.1|

Protein
Chain k, NADH-ubiquinone oxidoreductase chain 4L
Chain k, NADH-ubiquinone oxidoreductase chain 4L
gi|2431413449|pdb|7W4L|k

Protein
PhyC, partial [Protium costaricense]
PhyC, partial [Protium costaricense]
gi|641388093|gb|AIA58529.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278014	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001734339	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278014

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 23, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001734339

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 28, 2020)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Loss-of-function variants in ATM confer risk of gastric cancer.

Helgason H, Rafnar T, Olafsdottir HS, Jonasson JG, Sigurdsson A, Stacey SN, Jonasdottir A, Tryggvadottir L, Alexiusdottir K, Haraldsson A, le Roux L, Gudmundsson J, Johannsdottir H, Oddsson A, Gylfason A, Magnusson OT, Masson G, Jonsson T, Skuladottir H, Gudbjartsson DF, Thorsteinsdottir U, Sulem P, et al.

Nat Genet. 2015 Aug;47(8):906-10. doi: 10.1038/ng.3342. Epub 2015 Jun 22.

PubMed [citation]

PMID:: 26098866

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 Ambry Genetics, SCV000278014.7

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

Description

The p.S644* pathogenic mutation (also known as c.1931C>A), located in coding exon 12 of the ATM gene, results from a C to A substitution at nucleotide position 1931. This changes the amino acid from a serine to a stop codon within coding exon 12. This mutation has been reported in conjunction with a second pathogenic mutation in an individual with ataxia telangiectasia (A-T) (Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7) as well as in individuals with pancreatic cancer and in individuals with gastric cancer (Grant RC et al. Hum Genomics. 2013 Apr 5;7:11; Helgason H et al Nat. Genet. 2015 Aug;47(8):906-10). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001734339.1

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

Description

This variant changes 1 nucleotide in exon 13 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with pancreatic cancer (PMID: 23561644, 25479140) and has been shown to be associated with an increased risk of gastric cancer in the Icelandic population (PMID: 26098866). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 10817650). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Sep 29, 2024

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