11-108353828-A-G

Position:

• chr11-108353828-A-G

Variant summary

Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. BP2_Strong PP3

This summary comes from the ClinGen Evidence Repository: The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157198/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:25 B:3 O:2
• Conservation: PhyloP100: 3.98

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 Uncertain_significance. Variant got -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8734A>G	p.Arg2912Gly	missense_variant	60/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8734A>G	p.Arg2912Gly	missense_variant	60/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251450 Hom.: 1 AF XY: 0.000235 AC XY: 32 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461760 Hom.: 1 Cov.: 31 AF XY: 0.000198 AC XY: 144 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:25 Benign:3 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 19, 2022	The ATM c.8734A>G; p.Arg2912Gly variant (rs376676328), is reported in the literature in individuals affected with various forms of suspected hereditary cancer and suspected immunodeficiency (selected references: Teraoka 2001, Goldgar 2011, Young 2011, and Grossi 2021). However it has also been reported in trans with a pathogenic variant in individuals without signs of ataxia-telangiectasia (ClinGen VCEP). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (50 / 129,162 alleles, including 1 homozygotes) in the Genome Aggregation Database. The arginine at codon 2912 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.88). Due to conflicting information, the clinical significance of the p.Arg2912Gly variant is uncertain at this time. REFERENCES: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP: https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2560f0e1-9f2c-47aa-bea7-48edcf90c9a7 Goldgar et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. PMID: 21787400. Grossi et al. Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes (Basel). 2021 Aug 24;12(9):1299. PMID: 34573280. Teraoka et al. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer. 2001 Aug 1;92(3):479-87. PMID: 11505391. Young et al. Pancreatic cancer as a sentinel for hereditary cancer predisposition. BMC Cancer. 2018 Jun 27;18(1):697. doi: 10.1186/s12885-018-4573-5. PMID: 29945567. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 24728327, 30613976, 20346647, 21787400, 12673797, 25452441, 27443514, 26976419, 28135145, 28828701, 26787654, 26483394, 28093616, 28779002, 11505391, 12810666, 17166884, 29945567, 30197789, 28652578, 31159747, 32183364, 34426522, 33280026, 33471991, 33436325, 33910496, 34573280, 35047863, 35365198, 35886069, 34761457, 35475445, 36555667, 35029067, 36983044, 34326862, 31882575, Richardson2024[Preprint], 38701358, 38734904, 34262154, 23532176, 35534704) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ATM: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 31, 2018	In the published literature, this variant has been reported in affected individuals with breast (PMIDs: 33471991 (2021), 33280026 (2021), 31159747 (2019), 31882575 (2019), 28828701 (2017), 26976419 (2016), 11505391 (2001)), endometrial (PMID: 27443514 (2016)), pancreatic (PMID: 29945567 (2018)), prostate (PMID: 35886069 (2022)), or colorectal cancer (PMIDs: 34761457 (2022) and 30814645 (2019)), as well as melanoma (PMID: 36555667 (2022)). It has also been described in unaffected controls (PMIDs: 33471991 (2021) and 35365198 (2022)). The association of the variant with disease in different families is inconclusive (PMIDs 17166884 (2007) and 21787400 (2011)). In breast tumor sample, however, this variant was not identified as a driver of malignancy per LOH of the variant (PMID: 21787400 (2011)). Functional studies determined that this variant caused only a partial defect in ATM kinase activity upon CHEK1, however, other kinase targets studied as well as ATM protein expression and stability, were not affected (PMID: 17166884 (2007)). The frequency of this variant in the general population, 0.00039 (50/129162 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.8734A>G (p. Arg2912Gly) variant has an allele frequency of 0.00020 (0.02%, 54/268,310 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00039 (0.04%, 46/118,146 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). It is located in the PI3K domain, whose important role is highlighted by the fact that no missense variants with a minor allele frequency greater than 0.05% have been described in it (PM1_Supporting). 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: PP3 + PM1_Supporting (PMID: 33280026). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2023	This missense variant replaces arginine with glycine at codon 2912 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study reported that the variant may partially affect the kinase activity (PMID: 17166884). This variant has been reported in individuals affected with breast cancer (PMID: 11505391, 12673797, 12810666, 17166884, 21787400, 25452441, 26976419, 28779002, 28828701, 33471991, 35365198; DOI: 10.1186/s12859-021-04144-1), pancreatic cancer (PMID: 26483394, 29945567), colorectal cancer (PMID: 28135145, 30814645, 35029067), prostate cancer (PMID: 32183364, 35886069), endometrial cancer (PMID: 27443514), melanoma (PMID: 36555667), and chronic lymphocytic leukemia (PMID: 28652578). However it has also been observed in healthy individuals and controls (PMID: 21787400, 24728327, 28652578, 33471991). Breast cancer cases in the literature have been reported with pathogenic covariants in other genes (PMID: 12673797, 28828701) and with truncations in ATM (Color internal data). This variant has been identified in 58/282848 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2022	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. -

Familial cancer of breast Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 20, 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	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 12, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Ataxia-telangiectasia syndrome Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2912 of the ATM protein (p.Arg2912Gly). This variant is present in population databases (rs376676328, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer and/or other cancers (PMID: 12810666, 17166884, 21787400, 27443514, 28093616, 28828701, 30814645, 35047863). It has also been observed to segregate with disease in related individuals. This missense change has been observed to co-occur in individuals with a different variant in ATM that has been determined to be pathogenic (PMID: 12810666, 28828701; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 133641). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:3 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2023	Variant summary: ATM c.8734A>G (p.Arg2912Gly) results in a non-conservative amino acid change located in the catalytic domain (IPR044107) of 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 0.00029 in 253178 control chromosomes (gnomAD, Renault_2022), including 1 homozygote in the gnomAD database (of note, this individual is not included in the non-neuro dataset). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00029 vs 0.001), allowing no conclusion about variant significance. The variant has also been reported in 2/7325 European American women over the age of 70 with no personal history of cancer (FLOSSIES database). However, the variant c.8734A>G, has also been reported in the literature in numerous individuals affected with Breast and other cancer phenotypes (e.g. Bernstein_2003, Goldgar_2011, Pylkas_2007, Pylkas_2007, Ring_2016, Teraoka_2001, Thorstenson_2003, Thorstenson_2003, Young_2018, Zidan_2017, Rizzolo_2019, Tsaousis_2019, Jarhelle_2019, Rantapero_2020, Feliubadalo_2020, Karlsson_2021, Mikaeel_2022) as well as in an individual with immune deficiency (Grossi_2021). One of these reports demonstrated an incomplete co-segregation with disease, due to its presence in unaffected family members, as well as other affected family members who did not carry this variant (Pylkas_2007). In another report a co-occurrence with a pathogenic variant has been noted (BRCA1 c.68_69delAG, p.Glu23ValfsX17; Thorstenson_2003), providing supporting evidence for a benign role. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 39/60466 cases and in 30/53461 controls (Dorling_2021 through LOVD). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a partial defect in kinase activity, but normal ATM expression and protein stability, no dominant-negative effect and no increased sensitivity to irradiation (Pylkas_2007). The following publications have been ascertained in the context of this evaluation (PMID: 12673797, 25452441, 33471991, 33280026, 21787400, 34573280, 31882575, 33436325, 34761457, 17166884, 32183364, 35365198, 27443514, 30613976, 11505391, 12810666, 31159747, 29945567, 28828701). Multiple ClinVar submitters have assessed the variant since 2014 with a predominant consensus as VUS and some submitters citing overlapping evidence utilized in the context of this evaluation (VUS, n=19; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2020	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.8734A>G, in exon 60 that results in an amino acid change, p.Arg2912Gly. This sequence change has been described in the gnomAD database with a frequency of 0.039% in the European sub-population (dbSNP rs376676328). The p.Arg2912Gly change has been reported in an individual with endometrial cancer (PMID: 27443514), an individual with prostate cancer (PMID: 29945567), and families with breast cancer (PMID: 11505391, 12810666, 17166884). However, the p.Arg2912Gly change has also been observed in a family with a pathogenic BRCA1 variant (PMID: 12810666) and has shown incomplete segregation with the cancer phenotype in two breast cancer kindreds (PMID: 17166884). An in vitro functional study demonstrated that the p.Arg2912Gly change does not impact protein stability, but partially impacts ATM kinase activity (PMID: 17166884). The p.Arg2912Gly change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2912Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Arg2912Gly change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 23, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 06-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 27, 2023

- -

ATM-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

The ATM c.8734A>G variant is predicted to result in the amino acid substitution p.Arg2912Gly. The Arg2912 residue, located within the kinase domain of the ATM protein, has been highly conserved during evolution. This variant has been reported with a frequency of 0.038% among European (non-Finnish) individuals of unknown phenotype (including one homozygous individual) in a large population database, and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133641/). This variant has also been reported in multiple individuals with personal or family history of breast cancer (Teraoka et al. 2001, PubMed ID: 11505391; Thorstenson et al. 2003, PubMed ID: 12810666; Goldgar et al. 2011, Table S1, PubMed ID: 21787400; Couch et al. 2015, Table S6, PubMed ID: 25452441) and colorectal cancer (Yurgelun et al. 2017, PubMed ID: 28135145). However, Pylkäs et al. has reported incomplete segregation of this variant with familial breast cancer (Pylkäs et al. 2007, PubMed ID: 17166884). These authors further functionally demonstrated that the p.Arg2912Gly variant does not impair the phosphorylation of all the ATM substrates, indicating that a dominant-negative effect is unlikely for this variant. Taken together, although there is a possibility that the p.Arg2912Gly variant may impair protein-protein interactions associated with optimal ATM activity, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Arg2912Gly variant was identified in 7 of 8092 proband chromosomes (frequency: 0.0009) from Finnish (BRCA1/2 negative), Austrian, and American individuals or families with HBOC or breast cancer and was not identified in 7520 control chromosomes from healthy and unselected individuals (Tung 2016, Thorstenson 2003, Teraoka 2001, Pylkas 2007). In one study, 1 affected individual had the variant cooccurring with a pathogenic BRCA1 mutation (185delAG, 39stop) (Thorstenson 2003). In another study, segregation of the variant with cancer was not shown as several unaffected carriers occurred in the families of both positive cases (Pylkas 2007). Additionally, functional assays using LCL (lymphblastoid cell lines) demonstrated the variant to have similar protein expression levels to wildtype, and a partial defect in the phosphorylation of ATM substrates (Pylkas 2007). The variant was also identified in dbSNP (ID: rs376676328) “With Uncertain significance allele”, ClinVar (classified as uncertain significance; submitters: Invitae, Ambry Genetics, GeneDx, Color Genomics; and classification not provided by ITMI), Clinvitae (3x), and in control databases in 61 (1 homozygous) of 277204 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: Other in 1 of 6466 chromosomes (frequency: 0.0002), Latino in 1 of 34420 chromosomes (frequency: 0.00003), European Non-Finnish in 53 (1 homozygous) of 126696 chromosomes (frequency: 0.0004), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), European Finnish in 1 of 25794 chromosomes (frequency: 0.00004), and South Asian in 1 of 30782 chromosomes (frequency: 0.00003). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD, and GeneInsight – COGR (unavailable). The p.Arg2912 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MVP		0.96
MPC		0.66
ClinPred		0.78	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.92

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: rs376676328; hg19: chr11-108224555;