rs121434216

chr11-108345804-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000051.4(ATM):c.8480T>G(p.Phe2827Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F2827I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 8.00

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108345803-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186122.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-108345804-T-G is Pathogenic according to our data. Variant chr11-108345804-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3022.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.8480T>G	p.Phe2827Cys	missense_variant	58/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8480T>G	p.Phe2827Cys	missense_variant	58/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461578 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATM function (PMID: 9000145, 19431188, 25040471). 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. ClinVar contains an entry for this variant (Variation ID: 3022). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 8755918, 30549301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2827 of the ATM protein (p.Phe2827Cys). -

Ataxia - telangiectasia variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Observed in an individual with early-onset breast cancer (Akbar et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22529920, 23532176, 8789452, 27304073, 11826028, 15279807, 30665703, 17855419, 35710434, 25040471, 26896183, 30549301, 8755918, 19431188, 9000145) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 09, 2020

This missense variant replaces phenylalanine with cysteine at codon 2827 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). Functional studies have shown that this variant causes ATM protein to be unstable, resulting in a reduced kinase activity and DNA damage response (PMID: 19431188, 25040471). This variant has been observed in an individual affected with breast cancer (Color internal data). This variant has been reported in at least two individuals affected with mild form of autosomal recessive ataxia-telangiectasia in compound heterozygous state with a pathogenic truncation variant (PMID: 8755918, 9000145, 9463314, 15928302, 25040471, 30549301), indicating that this variant contributes to disease and appears to be hypomorphic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. Medical management should be considered based on the individual’s personal and family history. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 14, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 20, 2023

Variant summary: ATM c.8480T>G (p.Phe2827Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8480T>G has been reported in the literature in at least one individual affected with Ataxia-Telangiectasia, however all reports indicate the variant present in a UK patient with the same second allele, and therefore all reports appear to be of the same patient (McConville_1996, Jackson_2016, Schon_2019, Thompson_2005, Stankovic_1998). The variant was also reported in a patient with breast cancer in the heterozygous state (Akbar_2022). These data do not allow any conclusion about variant significance. In functional studies, despite being highly unstable, the variant retained relatively normal levels of kinase activity (near normal specific kinase activity; Barone_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.92		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		1.0
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.82

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: rs121434216; hg19: chr11-108216531; COSMIC: COSV53741029; COSMIC: COSV53741029;