rs748634900

Variant names:

• chr11-108343246-G-A
• rs748634900
• NM_000051.4:c.8293G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108343246-G-A
• chr11-108343246-G-C
• chr11-108343246-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM5 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.8293G>A​(p.Gly2765Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,724 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000216688: This alteration was also observed in 1/4112 breast cancer patients and 0/2399 healthy controls (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2765D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.49
• Publications: 15 publications found

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000216688: This alteration was also observed in 1/4112 breast cancer patients and 0/2399 healthy controls (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct; 85(4):427-46). This mutation has been reported in several patients with a clinical diagnosis of ataxia-telangiectasia, including a woman with ataxia-telangiectasia and breast cancer diagnosed under the age of 50 (Reiman A et al. Br. J. Cancer. 2011 Aug; 105(4):586-91; Taylor AM et al. Clin. Genet. 2014 Jul; Ambry Internal Data). This alteration was demonstrated to result in a protein product that lacks ATM kinase activity, is deficient at the G2/M checkpoint, and interferes with the phosphorylation activity of wild-type ATM (Izatt L et al.Genes Chromosomes Cancer. 1999 Dec; 26(4):286-94; Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30).; SCV002052637: Functional studies have shown that this variant protein has no detectable kinase activity and leads to cell cycle checkpoint defect in cell-based assays (PMID: 19431188).; SCV000253672: Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 21792198).; SCV000694377: Well controlled functional studies have shown the variant to lead to loss of ATM Kinase activity, while retaining almost complete ATM protein expression (Barone_2009, Reiman_2011).; SCV004931162: Functional studies indicate this variant impacts protein function [PMID: 21792198, 19431188].; SCV005443574: Published functional studies demonstrate a damaging effect: no detectable kinase activity and defective G2/M checkpoint (PMID: 19431188)
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108343247-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 628063.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-108343246-G-A is Pathogenic according to our data. Variant chr11-108343246-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 186351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.8293G>A	p.Gly2765Ser	missense	Exon 57 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8293G>A	p.Gly2765Ser	missense	Exon 58 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-34175C>T		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.8293G>A	p.Gly2765Ser	missense	Exon 57 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8293G>A	p.Gly2765Ser	missense	Exon 58 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1197-7954C>T		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251386 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Ataxia-telangiectasia syndrome (2)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.97		Gain of phosphorylation at G2765 (P = 0.2191)
MVP		0.98
MPC		0.58
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs748634900; hg19: chr11-108213973; COSMIC: COSV99069673; COSMIC: COSV99069673;