11-108304808-T-C

Position:

• chr11-108304808-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):​c.5630T>C​(p.Phe1877Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.526

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]

ATM (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035493374).
• BP6: Variant 11-108304808-T-C is Benign according to our data. Variant chr11-108304808-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5630T>C	p.Phe1877Ser	missense_variant	37/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5630T>C	p.Phe1877Ser	missense_variant	37/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249188 Hom.: 0 AF XY: 0.0000593 AC XY: 8 AN XY: 134966

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 SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461134 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 726940

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: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with non-Hodgkin lymphoma (Sipahimalani 2007); This variant is associated with the following publications: (PMID: 17640065) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant replaces phenylalanine with serine at codon 1877 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. In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with non-Hodgkin lymphoma (PMID: 17640065). This variant has been identified in 11/249188 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2019	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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Phe1877Ser variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs202028401) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx and Invitae), Clinvitae (2x), and in control databases in 11 of 244076 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European Non-Finnish in 1 of 110796 chromosomes (freq: 0.000009), and South Asian in 10 of 30752 chromosomes (freq: 0.0003); it was not observed in the African, “Other”, Latino, Ashkenazi Jewish, East Asian, European Finnish populations. The p.Phe1877Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.5630T>C (p.Phe1877Ser) variant in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Val151Met variant is observed in 0.004% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Phe at position 1877 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe1877Ser in ATM is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain significance. -

Ataxia-telangiectasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.2
DANN	Benign	0.60
DEOGEN2	Benign	0.093	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.36	T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.41	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.062
MutPred		0.47		Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);
MVP		0.47
MPC		0.22
ClinPred		0.015	T
GERP RS		-3.1
Varity_R		0.062
gMVP		0.12

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: rs202028401; hg19: chr11-108175535;