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NM_000051.4(ATM):c.2930G>A (p.Cys977Tyr) AND Ataxia-telangiectasia syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 30, 2024
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:
RCV000232860.10

Allele description [Variation Report for NM_000051.4(ATM):c.2930G>A (p.Cys977Tyr)]

NM_000051.4(ATM):c.2930G>A (p.Cys977Tyr)

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.2930G>A (p.Cys977Tyr)
HGVS:
  • NC_000011.10:g.108271259G>A
  • NG_009830.1:g.53428G>A
  • NM_000051.4:c.2930G>AMANE SELECT
  • NM_001351834.2:c.2930G>A
  • NP_000042.3:p.Cys977Tyr
  • NP_000042.3:p.Cys977Tyr
  • NP_001338763.1:p.Cys977Tyr
  • LRG_135t1:c.2930G>A
  • LRG_135:g.53428G>A
  • LRG_135p1:p.Cys977Tyr
  • NC_000011.9:g.108141986G>A
  • NM_000051.3:c.2930G>A
Protein change:
C977Y
Links:
dbSNP: rs876660628
NCBI 1000 Genomes Browser:
rs876660628
Molecular consequence:
  • NM_000051.4:c.2930G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.2930G>A - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000282917Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 30, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk.

Yu Y, Chang K, Chen JS, Bohlender RJ, Fowler J, Zhang D, Huang M, Chang P, Li Y, Wong J, Wang H, Gu J, Wu X, Schildkraut J, Cannon-Albright L, Ye Y, Zhao H, Hildebrandt MAT, Permuth JB, Li D, Scheet P, Huff CD.

HGG Adv. 2022 Jan 13;3(1):100078. doi: 10.1016/j.xhgg.2021.100078.

PubMed [citation]
PMID:
35047863
PMCID:
PMC8756505

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

Galatolo D, De Michele G, Silvestri G, Leuzzi V, Casali C, Musumeci O, Antenora A, Astrea G, Barghigiani M, Battini R, Battisti C, Caputi C, Cioffi E, De Michele G, Dotti MT, Fico T, Fiorillo C, Galosi S, Lieto M, Malandrini A, Melone MAB, Mignarri A, et al.

Int J Mol Sci. 2021 Aug 6;22(16). doi:pii: 8490. 10.3390/ijms22168490.

PubMed [citation]
PMID:
34445196
PMCID:
PMC8395181
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000282917.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 977 of the ATM protein (p.Cys977Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ataxia-telangiectasia and/or pancreatic cancer (PMID: 35047863; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 233765). 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 disruptive. This variant disrupts the p.Cys977 amino acid residue in ATM. Other variant(s) that disrupt this residue have been observed in individuals with ATM-related conditions (PMID: 34445196), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Feb 20, 2024