rs35963548

Positions:

• chr11-108251060-G-A
• chr11-108251060-G-C
• chr11-108251060-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5 BP4_Moderate BP6

The NM_000051.4(ATM):​c.1595G>A​(p.Cys532Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C532L?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:10 O:1
• Conservation: PhyloP100: 5.23

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108251060-G-TA is described in ClinVar as [Pathogenic]. Clinvar id is 1775998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1942927).
• BP6: Variant 11-108251060-G-A is Benign according to our data. Variant chr11-108251060-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133603.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=9, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.1595G>A	p.Cys532Tyr	missense_variant	10/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1595G>A	p.Cys532Tyr	missense_variant	10/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000256 AC: 64 AN: 250234 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135618

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461780 Hom.: 0 Cov.: 35 AF XY: 0.000168 AC XY: 122 AN XY: 727186

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74446

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.000344

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colorectal, and other cancers, as well as in unaffected controls (Camacho et al., 2002; Renwick et al., 2006; Hirsch et al., 2008; Tavtigian et al., 2009; Lu et al., 2015; Ballinger et al., 2016; Nadeu et al., 2016; Decker et al., 2017; Tavera-Tapia et al., 2017; Hauke et al., 2018; Martin-Morales et al., 2018; Paulo et al., 2018; Pastorino et al., 2020); This variant is associated with the following publications: (PMID: 20305132, 28779002, 29659569, 30256826, 16832357, 29522266, 11756177, 19781682, 17333338, 24728327, 27913932, 26689913, 22529920, 24356096, 27498913, 26837699, 30995915, 30303537, 31780696, 32325837, 33436325, 34646395, 35264596, 35495172, 34262154, 33128190, 33359728) -

not specified Uncertain:1 Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2021	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1595G>A, in exon 10 that results in an amino acid change, p.Cys532Tyr. This sequence change has been described in the gnomAD database with a frequency of 0.082% in the Latino/Admixed American subpopulation (dbSNP rs35963548). The p.Cys532Tyr change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys532Tyr substitution. This sequence change has been previously described in individuals with different types of cancers, an individual with a history of aplastic anemia or idiopathic pulmonary fibrosis, as well as in healthy individuals (PMID: 29659569, 31780696, 30303537, 28779002, 7913932, 29514593, 30256826, 30995915, FLOSSIES database https://whi.color.com/variant/11-108121787-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Cys532Tyr change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2024	Variant summary: ATM c.1595G>A (p.Cys532Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1615282 control chromosomes, predominantly at a frequency of 0.00088 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00018 vs 0.001), allowing no conclusion about variant significance. c.1595G>A has been reported in the literature in individuals affected with various types of cancer (example, breast, mantle cell lymphoma, head and neck squamous cell carcinoma), in settings of multigene panel testing in families negative for BRCA1/2, and in unaffected controls (example, Camacho_2002, Bernstein_2010, Tavtigian_2009, Lu_2015, Tavera-Tapia_2017, Dutil_2019, Girard_2019, Gomes_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 35980532, 20305132, 24728327, 11756177, 34262154, 31780696, 30303537, 33128190, 17333338, 26689913, 26837699, 37436117, 16832357, 27913932, 19781682). ClinVar contains an entry for this variant (Variation ID: 133603). Based on the evidence outlined above, the variant retained its classification as likely benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2021	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. -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Familial cancer of breast Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 30, 2024	This variant is considered likely benign. 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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 20, 2021	ACMG classification criteria: PS4 supporting -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Hepatoblastoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

-

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 05, 2023

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Cys532Tyr variant was identified in 1 of 13394 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and in 5 of 7392 control chromosomes (frequency: 0.001) from healthy individuals (Bernstein_2010_20305132, Bodian_2014_24728327, Hirsch_2008_ 17333338, Renwick_2006_16832357, Tavtigian_2009_19781682). In a study of ATM alterations in mantle cell lymphoma, the variant was identified in the tumours and normal tissue of affected individuals; in addition, healthy blood donors were found to carry the variant at frequencies similar to those of tumor patients, the variant thereby considered a polymorphism found frequently in healthy populations (Camacho 2002 11756177). The variant was also identified in dbSNP (ID: rs35963548) as “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Laboratory Corporation of America; uncertain significance by Invitae, Ambry Genetics, GeneDx, Fulgent Genetics; and classification not provided by ITMI), and Clinvitae (4x), and not in COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 66 of 276820 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24016 chromosomes (freq: 0.00008), Other in 10 of 6456 chromosomes (freq: 0.002), Latino in 27 of 34412 chromosomes (freq: 0.0008), and European Non-Finnish in 27 of 126410 chromosomes (freq: 0.0002), but not in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.2830A>T, p. p.Lys944X), increasing the likelihood the p.Cys532Tyr does not have clinical significance. The p.Cys532 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T;.
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.061	D
MutationAssessor	Uncertain	2.7	.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.37, 0.43
MVP		0.98
MPC		0.24
ClinPred		0.15	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.46
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35963548; hg19: chr11-108121787;