rs150757822

Positions:

• chr11-108312467-A-C
• chr11-108312467-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000051.4(ATM):​c.5975A>C​(p.Lys1992Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,590,620 control chromosomes in the GnomAD database, including 2 homozygotes. 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. K1992R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:17
• Conservation: PhyloP100: 6.29

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.02937448).
• BP6: Variant 11-108312467-A-C is Benign according to our data. Variant chr11-108312467-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127415.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=10, Benign=5}. Variant chr11-108312467-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5975A>C	p.Lys1992Thr	missense_variant	40/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5975A>C	p.Lys1992Thr	missense_variant	40/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251040 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000213 AC: 306 AN: 1438256 Hom.: 2 Cov.: 29 AF XY: 0.000211 AC XY: 151 AN XY: 716890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000420

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000474 Hom.: 1

Bravo AF: 0.000291

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 13, 2022	The ATM c.5975A>C (p.Lys1992Thr) missense change has a maximum subpopulation frequency of 0.43% in gnomAD v2.1.1. The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of breast cancer, prostate cancer, and pancreatic adenocarcinoma (PMID: 28767289, 30303537, 32601921, 33436325). In addition, four individuals with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 03, 2018	- -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	This variant is associated with the following publications: (PMID: 26580448, 17968022, 28652578, 21933854, 26689913, 23585524, 26787654, 24113346, 29769598, 29522266, 31159747, 30303537, 32601921, 33436325, 28767289) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 03, 2018	- -

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2023	Variant summary: ATM c.5975A>C (p.Lys1992Thr) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 273768 control chromosomes (gnomAD, publications, and FLOSSIES database), predominantly at a frequency of 0.0044 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), suggesting that the variant might be a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.5975A>C has been reported in the literature in individuals affected with cancer phenotypes including breast cancer, chronic lymphocytic leukemia, and pancreatic ductal adenocarcinoma, without strong evidence for causality (examples-Castillo-Guardiola_2022, Gervas_2022, Dorling_2021, Bernstein_2010, Skowronska_2011, Navrkalova_2013, Young_2016, Zhang_2015, Tung_2014, Shindo_2017, Tiao_2017, Girard_2019, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17968022, 20305132, 35245693, 33471991, 35763645, 30303537, 35264596, 26689913, 23585524, 28767289, 21933854, 28652578, 31159747, 25186627, 26787654, 26580448). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (benign, n=4; likely benign, n=7; VUS, n=9). Based on the evidence outlined above, the variant was classified as likely benign. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 12, 2022	This variant has been reported in the literature in numerous individuals with various types of cancer including breast, prostate and pancreatic ductal adenocarcinoma (Shindo 2017 PMID:28767289, Girard 2019 PMID:30303537, Tsaousis 2019 PMID:31159747, Gerbas 2020 PMID:32601921, Karlsson 2021 PMID:33436325). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.4% (45/10364) including 1 homozygote https://gnomad.broadinstitute.org/variant/11-108183194-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Benign (Variation ID:127415). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Lys1992Thr variant was identified in 1 of 636 proband chromosomes (frequency: 0.002) from British individuals or families with chronic lymphocytic leukemia and was present in 1 of 562 control chromosomes (frequency: 0.002) from healthy individuals (Skowronska 2012). The variant was also identified in dbSNP (ID: rs150757822) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae and Ambry Genetics) and Clinvitae (2X). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 92 (1 homozygous) of 277014 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Lys1992 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

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

Jun 13, 2023

- -

ATM-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 28, 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]. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jan 05, 2024

Homozygous in healthy individual. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls (PM2_sup), BP4 (supporting benign): REVEL: 0.256 BayesDEL:-0.143455, BS2 (strong benign): 1x homozygous in gnomAD (Ashkenazi Jewish), in Tübingen: NGSD counts: 1x hom, 30x het, 0x mosaic (homozygous: healthy mother in exom trio for other disease) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.26
Sift	Benign	0.054	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.73	P;P
Vest4		0.61
MVP		0.89
MPC		0.33
ClinPred		0.11	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs150757822; hg19: chr11-108183194; COSMIC: COSV53768482;