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NM_000051.4(ATM):c.4802G>A (p.Ser1601Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Mar 1, 2022
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:
RCV000131649.16

Allele description [Variation Report for NM_000051.4(ATM):c.4802G>A (p.Ser1601Asn)]

NM_000051.4(ATM):c.4802G>A (p.Ser1601Asn)

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.4802G>A (p.Ser1601Asn)
HGVS:
  • NC_000011.10:g.108294952G>A
  • NG_009830.1:g.77121G>A
  • NM_000051.4:c.4802G>AMANE SELECT
  • NM_001351834.2:c.4802G>A
  • NP_000042.3:p.Ser1601Asn
  • NP_000042.3:p.Ser1601Asn
  • NP_001338763.1:p.Ser1601Asn
  • LRG_135t1:c.4802G>A
  • LRG_135:g.77121G>A
  • LRG_135p1:p.Ser1601Asn
  • NC_000011.9:g.108165679G>A
  • NM_000051.3:c.4802G>A
  • p.S1601N
Protein change:
S1601N
Links:
dbSNP: rs587782506
NCBI 1000 Genomes Browser:
rs587782506
Molecular consequence:
  • NM_000051.4:c.4802G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.4802G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000186676Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely benign
(May 4, 2019)
germlineclinical testing

Citation Link,

SCV000910699Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely benign
(Apr 28, 2015)
germlineclinical testing

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

SCV001911462Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
criteria provided, single submitter

(Feliubadaló L et al. (Clin Chem 2021))
Uncertain significance
(Jun 17, 2020)
germlineclinical testing

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

SCV002535399Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Uncertain significance
(Mar 1, 2022)
germlinecuration

PubMed (5)
[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, curation
European caucasoidgermlineyes2not providednot provided2not 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

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]
PMID:
33471991
PMCID:
PMC7611105
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000186676.8

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

From Color Diagnostics, LLC DBA Color Health, SCV000910699.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911462.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1European caucasoid1not providednot providedclinical testing PubMed (1)
2European caucasoid1not providednot providedclinical testing PubMed (1)

Description

The c.4802G>A (p.Ser1601Asn) variant has an allele frequency of 0.000029 (0.003%, 7/236,740 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000058 (0.006%, 2/34,254 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided

From Sema4, Sema4, SCV002535399.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024