NM_000051.4(ATM):c.680C>T (p.Ser227Leu) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000796269.8

Allele description [Variation Report for NM_000051.4(ATM):c.680C>T (p.Ser227Leu)]

NM_000051.4(ATM):c.680C>T (p.Ser227Leu)

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.680C>T (p.Ser227Leu)

HGVS:

NC_000011.10:g.108244805C>T
NG_009830.1:g.26974C>T
NM_000051.4:c.680C>TMANE SELECT
NM_001351834.2:c.680C>T
NP_000042.3:p.Ser227Leu
NP_000042.3:p.Ser227Leu
NP_001338763.1:p.Ser227Leu
LRG_135t1:c.680C>T
LRG_135:g.26974C>T
LRG_135p1:p.Ser227Leu
NC_000011.9:g.108115532C>T
NM_000051.3:c.680C>T

Protein change:

S227L

Links:

dbSNP: rs762998620

NCBI 1000 Genomes Browser:

rs762998620

Molecular consequence:

NM_000051.4:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ataxia-telangiectasia syndrome (AT)
Synonyms:: Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000935774	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31159747, 33436325, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000935774

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Karlsson Q, Brook MN, Dadaev T, Wakerell S, Saunders EJ, Muir K, Neal DE, Giles GG, MacInnis RJ, Thibodeau SN, McDonnell SK, Cannon-Albright L, Teixeira MR, Paulo P, Cardoso M, Huff C, Li D, Yao Y, Scheet P, Permuth JB, Stanford JL, Dai JY, et al.

Eur Urol Oncol. 2021 Aug;4(4):570-579. doi: 10.1016/j.euo.2020.12.001. Epub 2021 Jan 9.

PubMed [citation]

PMID:: 33436325
PMCID:: PMC8381233

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935774.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 227 of the ATM protein (p.Ser227Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs762998620, gnomAD 0.007%). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer, or prostate cancer (PMID: 31159747, 33436325). ClinVar contains an entry for this variant (Variation ID: 485170). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change results in skipping of exon 7 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been 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: Nov 10, 2024

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