NM_000051.4(ATM):c.1903C>T (p.His635Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000562554.10

Allele description [Variation Report for NM_000051.4(ATM):c.1903C>T (p.His635Tyr)]

NM_000051.4(ATM):c.1903C>T (p.His635Tyr)

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.1903C>T (p.His635Tyr)

HGVS:

NC_000011.10:g.108253818C>T
NG_009830.1:g.35987C>T
NM_000051.4:c.1903C>TMANE SELECT
NM_001351834.2:c.1903C>T
NP_000042.3:p.His635Tyr
NP_000042.3:p.His635Tyr
NP_001338763.1:p.His635Tyr
LRG_135t1:c.1903C>T
LRG_135:g.35987C>T
LRG_135p1:p.His635Tyr
NC_000011.9:g.108124545C>T
NM_000051.3:c.1903C>T

Protein change:

H635Y

Links:

dbSNP: rs761491947

NCBI 1000 Genomes Browser:

rs761491947

Molecular consequence:

NM_000051.4:c.1903C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.1903C>T - 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

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Trim58 tripartite motif-containing 58 [Mus musculus]
Trim58 tripartite motif-containing 58 [Mus musculus]
Gene ID:216781

Gene
216781[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000665561	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000906634	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 27, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002533542	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jul 27, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 30093976, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000665561

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 18, 2023)

germline

clinical testing

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

Citation Link,

SCV000906634

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 27, 2019)

germline

clinical testing

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

SCV002533542

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jul 27, 2021)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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, curation

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

Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.

Chan GHJ, Ong PY, Low JJH, Kong HL, Ow SGW, Tan DSP, Lim YW, Lim SE, Lee SC.

Oncotarget. 2018 Jul 17;9(55):30649-30660. doi: 10.18632/oncotarget.25769.

PubMed [citation]

PMID:: 30093976
PMCID:: PMC6078133

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000665561.7

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

Description

The p.H635Y variant (also known as c.1903C>T), located in coding exon 12 of the ATM gene, results from a C to T substitution at nucleotide position 1903. The histidine at codon 635 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported as a variant of unknown significance in an individual with a personal history of ovarian cancer from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000906634.2

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

#	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

From Sema4, Sema4, SCV002533542.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	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: Sep 29, 2024

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