NM_000051.4(ATM):c.640del (p.Ser214fs) AND Ataxia-telangiectasia syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 16, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000169254.6

Allele description [Variation Report for NM_000051.4(ATM):c.640del (p.Ser214fs)]

NM_000051.4(ATM):c.640del (p.Ser214fs)

Gene:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.640del (p.Ser214fs)
HGVS:
  • NC_000011.10:g.108244096del
  • NC_000011.9:g.108114817del
  • NG_009830.1:g.26265del
  • NM_000051.3:c.640del
  • NM_000051.4:c.640delMANE SELECT
  • NM_001351834.2:c.640del
  • NP_000042.3:p.Ser214fs
  • NP_000042.3:p.Ser214fs
  • NP_001338763.1:p.Ser214fs
  • LRG_135t1:c.640del
  • LRG_135:g.26265del
  • LRG_135p1:p.Ser214fs
  • NC_000011.9:g.108114817del
  • NC_000011.9:g.108114823del
  • NC_000011.9:g.108114823delT
  • NM_000051.3:c.640delT
Protein change:
S214fs
Links:
dbSNP: rs786204543
NCBI 1000 Genomes Browser:
rs786204543
Molecular consequence:
  • NM_000051.3:c.640del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000051.4:c.640del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001351834.2:c.640del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220538Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 23, 2014)
unknownliterature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000748987Invitaecriteria provided, single submitter
Pathogenic
(Jul 21, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000838473Mendelicscriteria provided, single submitter
Pathogenic
(Jul 2, 2018)
unknownclinical testing

Citation Link,

SCV001448446Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 16, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing, literature only

Citations

PubMed

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry.

Graña B, Fachal L, Darder E, Balmaña J, Ramón Y Cajal T, Blanco I, Torres A, Lázaro C, Diez O, Alonso C, Santamariña M, Velasco A, Teulé A, Lasa A, Blanco A, Izquierdo A, Borràs J, Gutiérrez-Enríquez S, Vega A, Brunet J.

Breast Cancer Res Treat. 2011 Jul;128(2):573-9. doi: 10.1007/s10549-011-1462-x. Epub 2011 Mar 29.

PubMed [citation]
PMID:
21445571

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2.

PubMed [citation]
PMID:
26681312
PMCID:
PMC4985612
See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000220538.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000748987.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Ser214Profs*16) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous and compound heterozygous states in several individuals affected with ataxia-telangiectasia (PMID: 8789452, 21965147, 12815592, 15039971). It has also been observed in the heterozygous state in individuals affected with breast cancer or referred for cancer panel testing (PMID: 21445571, 26681312). ClinVar contains an entry for this variant (Variation ID: 188895). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV000838473.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001448446.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: ATM c.640delT (p.Ser214ProfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251182 control chromosomes. c.640delT has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (e.g. Byrd_1996, Mitui_2003, Coutinho_2004, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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