rs377065665

chr11-108289694-C-Achr11-108289694-C-Gchr11-108289694-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000051.4(ATM):c.4329C>A(p.His1443Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1443Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: -0.558

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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, 16 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.2452913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4329C>A	p.His1443Gln	missense_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4329C>A	p.His1443Gln	missense_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250910 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135624

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000958 AC: 14 AN: 1461140 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726876

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74400

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1443 of the ATM protein (p.His1443Gln). This variant is present in population databases (rs377065665, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 31871109). ClinVar contains an entry for this variant (Variation ID: 185311). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 19, 2023	This missense variant replaces histidine with glutamine at codon 1443 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282294 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	clinical testing	Ambry Genetics	Dec 07, 2022	The p.H1443Q variant (also known as c.4329C>A), located in coding exon 28 of the ATM gene, results from a C to A substitution at nucleotide position 4329. The histidine at codon 1443 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 08, 2024

Variant summary: ATM c.4329C>A (p.His1443Gln) results in a non-conservative amino acid change in 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 1.2e-05 in 250910 control chromosomes, predominantly at a frequency of 6.2e-05 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.4329C>A has not been reported in the literature in individuals affected with Ataxia-Telangiectasia and 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: 31871109, 33471991). ClinVar contains an entry for this variant (Variation ID: 185311). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATM-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2022

The ATM c.4329C>A variant is predicted to result in the amino acid substitution p.His1443Gln. This variant has been reported in multiple individuals with breast cancer (Adedokun et al 2020. PubMed ID: 31871109; Eygelaar et al 2022. PubMed ID: 35039564). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160421-C-A). This variant has been interpreted as uncertain by multiple groups in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185311). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Eygelaar et al., 2022); This variant is associated with the following publications: (PMID: 31871109, 36452878, 33471991, 35039564) -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Benign	0.095	T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.21	T;T;D
Polyphen		0.38	B;B;.
Vest4		0.31
MutPred		0.39		Gain of MoRF binding (P = 0.0915);Gain of MoRF binding (P = 0.0915);.;
MVP		0.76
MPC		0.13
ClinPred		0.18	T
GERP RS		-1.6
Varity_R		0.54
gMVP		0.48

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: rs377065665; hg19: chr11-108160421;