U.S. flag

An official website of the United States government

NM_000051.4(ATM):c.4888G>A (p.Asp1630Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Feb 9, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000562636.8

Allele description [Variation Report for NM_000051.4(ATM):c.4888G>A (p.Asp1630Asn)]

NM_000051.4(ATM):c.4888G>A (p.Asp1630Asn)

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.4888G>A (p.Asp1630Asn)
HGVS:
  • NC_000011.10:g.108295038G>A
  • NG_009830.1:g.77207G>A
  • NM_000051.4:c.4888G>AMANE SELECT
  • NM_001351834.2:c.4888G>A
  • NP_000042.3:p.Asp1630Asn
  • NP_000042.3:p.Asp1630Asn
  • NP_001338763.1:p.Asp1630Asn
  • LRG_135t1:c.4888G>A
  • LRG_135:g.77207G>A
  • LRG_135p1:p.Asp1630Asn
  • NC_000011.9:g.108165765G>A
  • NM_000051.3:c.4888G>A
Protein change:
D1630N
Links:
dbSNP: rs1555101921
NCBI 1000 Genomes Browser:
rs1555101921
Molecular consequence:
  • NM_000051.4:c.4888G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.4888G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000668103Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 28, 2022) 		germlineclinical testing

Citation Link,

SCV001352887Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 9, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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, SCV000668103.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.4888G>A variant (also known as p.D1630N), located in coding exon 31 of the ATM gene, results from a G to A substitution at nucleotide position 4888. The aspartic acid at codon 1630 is replaced by asparagine, an amino acid with highly similar properties. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

From Color Diagnostics, LLC DBA Color Health, SCV001352887.3

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

Description

This missense variant replaces aspartic acid with asparagine at codon 1630 of the ATM protein. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000668103.4). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 8, 2024