NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 5, 2024
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:: RCV000220834.18

Allele description [Variation Report for NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)]

NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.6848C>T (p.Ser2283Leu)

HGVS:

NC_000011.10:g.108326098C>T
NG_009830.1:g.108267C>T
NG_054724.1:g.148735G>A
NM_000051.4:c.6848C>TMANE SELECT
NM_001330368.2:c.641-17027G>A
NM_001351110.2:c.*38+9122G>A
NM_001351834.2:c.6848C>T
NP_000042.3:p.Ser2283Leu
NP_000042.3:p.Ser2283Leu
NP_001338763.1:p.Ser2283Leu
LRG_135t1:c.6848C>T
LRG_135:g.108267C>T
LRG_135p1:p.Ser2283Leu
NC_000011.9:g.108196825C>T
NM_000051.3:c.6848C>T

Protein change:

S2283L

Links:

dbSNP: rs876660730

NCBI 1000 Genomes Browser:

rs876660730

Molecular consequence:

NM_001330368.2:c.641-17027G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+9122G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6848C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278383	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 5, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33280026, 35264596 Citation Link,
SCV000904845	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001911478	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	criteria provided, single submitter (Feliubadaló L et al. (Clin Chem 2021))	Uncertain significance (Jun 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278383

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 5, 2024)

germline

clinical testing

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

Citation Link,

SCV000904845

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 26, 2021)

germline

clinical testing

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

SCV001911478

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

criteria provided, single submitter

(Feliubadaló L et al. (Clin Chem 2021))

Uncertain significance
(Jun 17, 2020)

germline

clinical testing

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

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
European caucasoid	germline	yes	2	not provided	not provided	2	not provided	clinical testing

Citations

PubMed

Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.

Guindalini RSC, Viana DV, Kitajima JPFW, Rocha VM, López RVM, Zheng Y, Freitas É, Monteiro FPM, Valim A, Schlesinger D, Kok F, Olopade OI, Folgueira MAAK.

Sci Rep. 2022 Mar 9;12(1):4190. doi: 10.1038/s41598-022-07383-1.

PubMed [citation]

PMID:: 35264596
PMCID:: PMC8907244

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000278383.7

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

Description

The p.S2283L variant (also known as c.6848C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6848. The serine at codon 2283 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in a patient with ovarian cancer and a patient with sebaceous adenoma in a cohort of 766 ATM variant carriers and classified as a variant of uncertain significance (Feliubadaló L et al. Clin Chem, 2021 Mar;67:518-533). This variant was also present in 1 of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well 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, SCV000904845.2

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

Description

This missense variant replaces serine with leucine at codon 2283 of the ATM protein. 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 hereditary cancer 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.

#	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 Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911478.1

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

Description

Carrier of an heterozygous pathogenic variant in MSH2

Description

The c.6848C>T (p.Ser2283Leu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or 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 PROVEAN (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: PM2 + BP4 (PMID: 33280026).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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