VCV000003048.92 - ClinVar

NM_000051.4(ATM):c.146C>G (p.Ser49Cys)

Germline

Top reviewed classifications are shown here.

Submission summary:

35 submissions

35 submitters

9 conditions

Reviewed by expert panel

Benign

Mar 2022 by ClinGen Heredi… FDA Recognized Database

for Familial cancer of breast

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000051.4(ATM):c.146C>G (p.Ser49Cys)

Variation ID: 3048 Accession: VCV000003048.92

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108227849 (GRCh38) [ NCBI UCSC ] 11: 108098576 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Oct 20, 2024	Mar 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.146C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Ser49Cys	missense
NM_001351834.2:c.146C>G	NP_001338763.1:p.Ser49Cys	missense
NM_001351835.2:c.146C>G	NP_001338764.1:p.Ser49Cys	missense
NM_001351836.2:c.146C>G	NP_001338765.1:p.Ser49Cys	missense
NC_000011.10:g.108227849C>G
NC_000011.9:g.108098576C>G
NG_009830.1:g.10018C>G
LRG_135:g.10018C>G
LRG_135t1:c.146C>G	LRG_135p1:p.Ser49Cys
	Q13315:p.Ser49Cys

... more HGVS ... less HGVS

Protein change

S49C

Other names

p.S49C:TCC>TGC
NM_000051.3(ATM):c.146C>G
NP_000042.3:p.Ser49Cys

Canonical SPDI

NC_000011.10:108227848:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00419 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00419

1000 Genomes Project 30x 0.00484

The Genome Aggregation Database (gnomAD), exomes 0.00712

Exome Aggregation Consortium (ExAC) 0.00737

Trans-Omics for Precision Medicine (TOPMed) 0.00776

Links

ClinGen: CA202190 UniProtKB: Q13315#VAR_010798 OMIM: 607585.0032 dbSNP: rs1800054 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10852	17462

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast cancer, susceptibility to	risk factor (1)	no assertion criteria provided	Jun 1, 2006	RCV000003189.11
Hereditary cancer-predisposing syndrome	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jun 8, 2020	RCV000128940.18
Ataxia-telangiectasia syndrome	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000122818.34
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000176968.36
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000224620.45
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001357240.10
Tip-toe gait	Uncertain significance (1)	criteria provided, single submitter	Oct 6, 2020	RCV001353116.9
Hereditary breast ovarian cancer syndrome	Benign (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225258.9
Familial cancer of breast	Benign (3)	reviewed by expert panel	Mar 9, 2022	RCV002221467.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Mar 09, 2022)	reviewed by expert panel (clingen hbop acmg specifications atm v1-1) Method: curation	Familial cancer of breast (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV002499279.1 First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0ea617e8-2bed-480f-9f56-843da825a738 Comment: The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). … (more) The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (less)
Likely Benign (Sep 28, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280894.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000301652.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821790.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Benign (Feb 27, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000228761.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Benign (Feb 16, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000916542.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (6) PubMed: 16652348‚ 20826828‚ 23585524‚ 11897820‚ 16998505‚ 9887333 Comment: Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded … (more) Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277324 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.013 in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold above the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). The allele frequency of this variant in a cohort of individuals who are cancer-free and older than 70 years is 0.025 (185/7325), which is even higher than the allele frequency in the general controls (gnomAD Non-Finnish European, 0.013). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.146C>G variant has been reported in the literature in individuals affected with Breast Cancer, though one study reported a lack of cosegregation of the variant with disease in two family members of a proband (Allinen_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. A case control study seeking to evaluate whether the variant increases the risk of breast cancer raised the possibility that the variant may be a breast cancer susceptibility allele (Stredrick_2006). However, a much larger cohort from Fletcher_2012 failed to prove the same. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001750295.1 First in ClinVar: Jul 16, 2021 Last updated: Jul 16, 2021	Sex: mixed
Benign (May 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593473.2 First in ClinVar: Oct 02, 2016 Last updated: Jan 29, 2022
Benign (Jun 08, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530420.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (May 07, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002047167.2 First in ClinVar: Jan 03, 2022 Last updated: Dec 31, 2022	Publications: PubMed (32) PubMed: 16652348‚ 18565893‚ 22438227‚ 17203191‚ 15928302‚ 12708462‚ 17293864‚ 18164969‚ 22420423‚ 12673797‚ 12149228‚ 21396839‚ 9887333‚ 20111735‚ 11078475‚ 19081671‚ 19347964‚ 10534763‚ 11606401‚ 12917204‚ 2677459‚ 26854966‚ 26774591‚ 31429931‚ 27599564‚ 24416720‚ 22995991‚ 8797579‚ 10425038‚ 10873394‚ 11897822‚ 15042666
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016475.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002549985.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166075.13 First in ClinVar: Jun 15, 2014 Last updated: Feb 28, 2024
Benign (Apr 17, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV005083844.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 25085752 Comment: This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more) This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005230989.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Dec 08, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000537372.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Likely benign (Feb 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV000576455.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Benign (Oct 03, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167079.11 First in ClinVar: Jun 23, 2014 Last updated: Sep 28, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Oct 09, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743718.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001265964.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Uncertain significance (Oct 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tip-toe gait Affected status: yes Allele origin: unknown	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV001548277.1 First in ClinVar: Apr 02, 2021 Last updated: Apr 02, 2021	Clinical Features: limited range of motion of the upper ankle (present) Zygosity: Single Heterozygote Age: 0-9 years Sex: male Method: Gene panel analysis
Benign (May 07, 2021)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001880725.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (32) PubMed: 16652348‚ 18565893‚ 22438227‚ 17203191‚ 15928302‚ 12708462‚ 17293864‚ 18164969‚ 22420423‚ 12673797‚ 12149228‚ 21396839‚ 9887333‚ 20111735‚ 11078475‚ 19081671‚ 19347964‚ 10534763‚ 11606401‚ 12917204‚ 2677459‚ 26854966‚ 26774591‚ 31429931‚ 27599564‚ 24416720‚ 22995991‚ 8797579‚ 10425038‚ 10873394‚ 11897822‚ 15042666
Benign (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002504913.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022	Number of individuals with the variant: 3 Geographic origin: South Africa
Benign (Sep 28, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602555.9 First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024
Benign (Jun 19, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000172814.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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. (less)
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493597.33 First in ClinVar: Jun 08, 2016 Last updated: Oct 20, 2024	Comment: ATM: BP4, BS1, BS2 Number of individuals with the variant: 91
risk factor (Jun 01, 2006)	no assertion criteria provided Method: literature only	BREAST CANCER, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023347.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016	Publications: PubMed (3) PubMed: 16652348‚ 12362033‚ 15042666 Comment on evidence: Stredrick et al. (2006) presented analyses which, they suggested, provided the most convincing evidence to that time that missense mutations in ATM, particularly ser49 to … (more) Stredrick et al. (2006) presented analyses which, they suggested, provided the most convincing evidence to that time that missense mutations in ATM, particularly ser49 to cys (S49C, 146C-G), may be breast cancer (114480) susceptibility alleles. Among subjects in the United States, 3.9% of breast cancer cases and 2.6% of controls were heterozygous for S49C, while in Polish subjects 2.3% of cases and 1.2% of controls carried this mutation, with a combined odds ratio of 1.69 (95% CI, 1.19-2.40; P = 0.004). Previous studies had identified this variant more commonly in breast cancer patients (e.g., Maillet et al., 2002; Buchholz et al., 2004). (less)
Benign (Nov 20, 2015)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745800.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800448.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (Nov 14, 2019)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088221.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Likely benign (Feb 14, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000787844.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552651.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and … (more) The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and was present in 58 of 7048 control chromosomes (frequency: 0.008) from healthy individuals (Castellvi-Bei 1999, Petereit 2013, Schneider 2006, Stedrick 2006). The variant was identified in dbSNP (rs1800054) as â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Color, Ambry Genetics, Invitae and 6 other submitters and likely benign by True Health Diagnostics, University of Chicago and 5 other submitters) and LOVD 3.0 (observed 10x). The variant was identified in control databases in 2005 of 276,924 chromosomes (12 homozygous) at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 65 of 24,012 chromosomes (freq: 0.003), Other in 30 of 6462 chromosomes (freq: 0.005), Latino in 105 of 34,412 chromosomes (freq: 0.003), European in 1615 of 126,588 chromosomes (freq: 0.01), Ashkenazi Jewish in 6 of 10,148 chromosomes (freq: 0.0006), Finnish in 67 of 25,760 chromosomes (freq: 0.003) and South Asian in 117 of 30,674 chromosomes (freq: 0.004). The variant was not observed in the East Asian population. The variant was expressed in vitro and had reduced but detectable levels of ATM (Becker-Catania 2000). The p.Ser49 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001905812.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924571.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952636.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

Comment:

Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277324 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.013 in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold above the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). The allele frequency of this variant in a cohort of individuals who are cancer-free and older than 70 years is 0.025 (185/7325), which is even higher than the allele frequency in the general controls (gnomAD Non-Finnish European, 0.013). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.146C>G variant has been reported in the literature in individuals affected with Breast Cancer, though one study reported a lack of cosegregation of the variant with disease in two family members of a proband (Allinen_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. A case control study seeking to evaluate whether the variant increases the risk of breast cancer raised the possibility that the variant may be a breast cancer susceptibility allele (Stredrick_2006). However, a much larger cohort from Fletcher_2012 failed to prove the same. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Comment:

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This alteration is classified as 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.

Comment:

The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and was present in 58 of 7048 control chromosomes (frequency: 0.008) from healthy individuals (Castellvi-Bei 1999, Petereit 2013, Schneider 2006, Stedrick 2006). The variant was identified in dbSNP (rs1800054) as â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Color, Ambry Genetics, Invitae and 6 other submitters and likely benign by True Health Diagnostics, University of Chicago and 5 other submitters) and LOVD 3.0 (observed 10x). The variant was identified in control databases in 2005 of 276,924 chromosomes (12 homozygous) at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 65 of 24,012 chromosomes (freq: 0.003), Other in 30 of 6462 chromosomes (freq: 0.005), Latino in 105 of 34,412 chromosomes (freq: 0.003), European in 1615 of 126,588 chromosomes (freq: 0.01), Ashkenazi Jewish in 6 of 10,148 chromosomes (freq: 0.0006), Finnish in 67 of 25,760 chromosomes (freq: 0.003) and South Asian in 117 of 30,674 chromosomes (freq: 0.004). The variant was not observed in the East Asian population. The variant was expressed in vitro and had reduced but detectable levels of ATM (Becker-Catania 2000). The p.Ser49 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.	Shakya S	Clinical genetics	2019	PMID: 31429931
Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer.	Prodosmo A	Journal of experimental & clinical cancer research : CR	2016	PMID: 27599564
A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.	Spoerri L	Pigment cell & melanoma research	2016	PMID: 26854966
Next generation sequencing revealed DNA ligase IV deficiency in a "developmentally normal" patient with massive brain Epstein-Barr virus-positive diffuse large B-cell lymphoma.	Sharapova SO	Clinical immunology (Orlando, Fla.)	2016	PMID: 26774591
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.	Pruss D	Breast cancer research and treatment	2014	PMID: 25085752
Prevalence of ATM Sequence Variants in Northern Plains American Indian Cancer Patients.	Petereit DG	Frontiers in oncology	2013	PMID: 24416720
ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin.	Navrkalova V	Haematologica	2013	PMID: 23585524
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Apoptosis gene polymorphisms and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy.	Meyer A	Urologic oncology	2013	PMID: 21396839
Functional variations in the ATM gene and susceptibility to differentiated thyroid carcinoma.	Xu L	The Journal of clinical endocrinology and metabolism	2012	PMID: 22438227
Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.	Knappskog S	Breast cancer research : BCR	2012	PMID: 22420423
Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.	Fletcher O	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2010	PMID: 20826828
Germline mutations and polymorphisms in the origins of cancers in women.	Hirshfield KM	Journal of oncology	2010	PMID: 20111735
Description and validation of high-throughput simultaneous genotyping and mutation scanning by high-resolution melting curve analysis.	Nguyen-Dumont T	Human mutation	2009	PMID: 19347964
Cancer driver mutations in protein kinase genes.	Torkamani A	Cancer letters	2009	PMID: 19081671
Risk of cancer by ATM missense mutations in the general population.	Dombernowsky SL	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18565893
Detection of ATM gene mutations in young lung cancer patients: a population-based control study.	Schneider J	Archives of medical research	2008	PMID: 18164969
A common coding variant in CASP8 is associated with breast cancer risk.	Cox A	Nature genetics	2007	PMID: 17293864
ATM gene mutations in former uranium miners of SDAG Wismut: a pilot study.	Schneider J	Oncology reports	2007	PMID: 17203191
ATM and breast cancer susceptibility.	Ahmed M	Oncogene	2006	PMID: 16998505
The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.	Stredrick DL	Human mutation	2006	PMID: 16652348
Cancer risks and mortality in heterozygous ATM mutation carriers.	Thompson D	Journal of the National Cancer Institute	2005	PMID: 15928302
A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls.	Buchholz TA	Cancer	2004	PMID: 15042666
The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.	Bretsky P	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2003	PMID: 12917204
Resolving ATM haplotypes in whites.	Letrero R	American journal of human genetics	2003	PMID: 12708462
Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer.	Bernstein JL	Human mutation	2003	PMID: 12673797
Constitutional alterations of the ATM gene in early onset sporadic breast cancer.	Maillet P	Journal of medical genetics	2002	PMID: 12362033
ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma.	Grønbaek K	Blood	2002	PMID: 12149228
ATM mutations in Finnish breast cancer patients.	Allinen M	Journal of medical genetics	2002	PMID: 11897822
A novel locus for brachydactyly type A1 on chromosome 5p13.3-p13.2.	Armour CM	Journal of medical genetics	2002	PMID: 11897820
Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.	Dörk T	Cancer research	2001	PMID: 11606401
Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.	Bonnen PE	American journal of human genetics	2000	PMID: 11078475
Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity.	Becker-Catania SG	Molecular genetics and metabolism	2000	PMID: 10873394
Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer.	Izatt L	Genes, chromosomes & cancer	1999	PMID: 10534763
New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.	Castellví-Bel S	Human mutation	1999	PMID: 10425038
Characterization of ATM gene mutations in 66 ataxia telangiectasia families.	Sandoval N	Human molecular genetics	1999	PMID: 9887333
ATM mutations in cancer families.	Vorechovský I	Cancer research	1996	PMID: 8797579
Juvenile parkinsonism with marked diurnal fluctuation.	Yamada T	The Japanese journal of psychiatry and neurology	1989	PMID: 2677459
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATM	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0ea617e8-2bed-480f-9f56-843da825a738	-	-	-	-
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Text-mined citations for rs1800054 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.146C>G (p.Ser49Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1800054 ...