rs4988125

Positions:

• chr11-108332892-C-G
• chr11-108332892-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The ATM c.7919C>G (p.Thr2640Ser) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico predictors for this alteration (Align GVGD: C55; REVEL: 0.117) are indeterminate. 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/CA10579274/MONDO:0016419/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 0.270

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 1 ACMG points.

• PM2: 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.7919C>G	p.Thr2640Ser	missense_variant	53/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7919C>G	p.Thr2640Ser	missense_variant	53/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Uncertain:1

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.7919C>G (p.Thr2640Ser) variant is absent in GnomAD v2.1.1 (PM2_Supporting). In silico predictors for this alteration (Align GVGD: C55; REVEL: 0.117) are indeterminate. 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.84
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.57	T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.46	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.12
Sift	Benign	0.64	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0020	B;B
Vest4		0.044
MutPred		0.22		Loss of ubiquitination at K2639 (P = 0.1037);Loss of ubiquitination at K2639 (P = 0.1037);
MVP		0.66
MPC		0.11
ClinPred		0.095	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4988125; hg19: chr11-108203619;