rs140856217
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):c.4709T>C(p.Val1570Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. V1570I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.4709T>C | p.Val1570Ala | missense | Exon 31 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.4709T>C | p.Val1570Ala | missense | Exon 32 of 64 | NP_001338763.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.4709T>C | p.Val1570Ala | missense | Exon 31 of 63 | ENSP00000501606.1 | ||
| ATM | ENST00000452508.7 | TSL:1 | c.4709T>C | p.Val1570Ala | missense | Exon 32 of 64 | ENSP00000388058.2 | ||
| ATM | ENST00000531525.3 | TSL:1 | c.4437-1517T>C | intron | N/A | ENSP00000434327.3 |
Frequencies
GnomAD3 genomes 0.000434 AC: 66AN: 152136Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.000410 AC: 103AN: 250980 AF XY: 0.000391 show subpopulations
GnomAD4 exome AF: 0.000387 AC: 565AN: 1459806Hom.: 0 Cov.: 30 AF XY: 0.000365 AC XY: 265AN XY: 726414 show subpopulations
Age Distribution
GnomAD4 genome 0.000433 AC: 66AN: 152254Hom.: 0 Cov.: 30 AF XY: 0.000403 AC XY: 30AN XY: 74460 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:8
ATM: PM2, BP4
This variant is denoted ATM c.4709T>C at the cDNA level, p.Val1570Ala (V1570A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been reported in several individuals with breast cancer, one with prostate cancer, and at least one with advanced cancer of unspecified type, as well as in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Izatt 1999, Dork 2001, Pugh 2009, Tavtigian 2009, Yurgelun 2015, Maxwell, 2016, Tung 2016, Mandelker 2017). In one family, the variant was identified in both a proband with early onset breast cancer and her mother, who also had a history of breast cancer (Izatt 1999). ATM Val1570Ala was observed at an allele frequency of 0.07% (91/126,354) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val1570Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ataxia-telangiectasia syndrome Uncertain:3Benign:4
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
not specified Uncertain:1Benign:4
Variant summary: ATM c.4709T>C (p.Val1570Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251524 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00041 vs 0.001), allowing no conclusion about variant significance. c.4709T>C has been reported in the literature as a VUS/likely benign variant in settings of multigene panel testing on individuals affected with various cancer phenotypes (e.g. Izatt, 1999, Dork_2001, Gumy-Pause_2006, Bernstein_2010, Haiman_2013, Maxwell_2016, Grasel_2020, Bandeira_2021) without strong evidence for causality. One of these studies reported this variant within settings of loss of heterozygosity (LOH) of the normal allele in a family where it did not clearly segregate with cancer (Grasel_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=7; VUS, n=10). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. At-least one submitter reports a non-specified co-occurrence with mutation in same gene (phase unknown) as a basis of their likely benign classification. Based on the evidence outlined above, the variant was classified as benign.
Hereditary cancer-predisposing syndrome Benign:5
BS1, BP4 c.4709T>C, located in exon 31 of the ATM gene, is predicted to result in the substitution of Val by Ala at codon 1570, p.(Val1570Ala).The variant allele was found in 86/117848 alleles, with a filter allele frequency of 0.061% at 95% confidence, within the European (non-Finnish) population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.152) suggests that it does not affect the protein function (BP4). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. This variant has been reported in ClinVar (6x likely benign, 13x likely benign, 12x uncertain significance) and LOVD (8x likely benign, 2x NA, 1x likely pathogenic) databases. Based on currently available information, the variant c.4709T>C should be considered a likely benign variant.
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.
Familial cancer of breast Uncertain:1Benign:1
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
This variant was classified as: Uncertain significance.
Breast and/or ovarian cancer Uncertain:1
ATM-related disorder Uncertain:1
The ATM c.4709T>C variant is predicted to result in the amino acid substitution p.Val1570Ala. This variant has been reported in at least one study to segregate with breast cancer in a first-degree relative of the proband (Table 3, Izatt et al. 1999. PubMed ID: 10534763). It has also been reported in several individuals with a history of breast cancer (Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Tung et al. 2016. PubMed ID: 26976419), as well as in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), but was classified as a variant of uncertain significance. It was also found as a recurring variant in patients with chronic lymphocytic leukemia (Tiao et al. 2017. PubMed ID: 28652578) as well as in individuals with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127394/). At this time, we classify the clinical significance of this variant as uncertain due to the absence of conclusive functional and genetic evidence.
Malignant tumor of breast Uncertain:1
The ATM p.Val1570Ala variant was identified in 7 of 12586 proband chromosomes (frequency: 0.0005) from U.S., Canadian, German and British individuals or families with breast cancer, Lynch syndrome or prostate cancer and was not identified in 4998 control chromosomes from healthy individuals (Tavtigian 2009, Tung 2016, Izzat 2009, Dork 2001, Yurgelin 2015, Pugh 2009). The variant was also identified in dbSNP (ID: rs140856217) as “With Uncertain significance allele”, ClinVar and Clinvitae (1x classified as likely benign by Ambry Genetics, 2x uncertain significance by GeneDx and Invitae). The variant was not identified in the COGR, COSMIC, MutDB, or the LOVD 3.0 databases. The variant was identified in control databases in 112 of 276738 chromosomes at a frequency of 0.0004 in the following populations: European non-Finnish 91 of 126354 chromosomes (freq. 0.0007); “Other” in 3 of 6464 chromosomes (freq. 0.0005); Latino in 15 of 34400 chromosomes (freq. 0.0004); European Finnish in 2 of 25720 chromosomes (freq. 0.00008); African in 1 of 24028 chromosomes (freq. 0.00004) (Genome Aggregation Consortium Feb 27, 2017). This variant was found in one British individual with: two separate primary early-onset breast cancers, segregation with one family member with breast cancer (mother), loss of heterozygosity for ATM and neighbouring loci in tumour DNA, and sensitivity reaction to radiotherapy, however the authors conclude that this may represent a rare polymorphism because the residue is not conserved in mouse and they did not perceive that the variant was found in a functional domain (Izzat 2009). The p.Val1570Ala residue is not conserved in mammals and 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Hereditary breast ovarian cancer syndrome Benign:1
BP4_Moderate+BP1+PM2_Supporting+PP1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at