rs139552233
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BP2_StrongPP3BS1
This summary comes from the ClinGen Evidence Repository: The c.2932T>C variant in ATM is a missense variant predicted to cause substitution of serine by proline at amino acid 978 (p.Ser978Pro). This variant has been observed with the variant c.8395_8404del (p.F2799Kfs*4) which is classified as pathogenic by the HBOP VCEP (ClinVar SCV005627268.1) in one individual with Ataxia-Telangiectasia and 6 individuals with no features of Ataxia-Telangiectasia (PMID:26896183, Ambry internal data) (PM3/BP2 points: +2). The phase of the variants was suspected to be in cis by family testing. This variant has also been observed with other pathogenic ATM variants in 21 individuals with no features of Ataxia-Telangiectasia (Ambry internal data) (PM3/BP2 points: -42) (BP2_Strong met, -40 points). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004874 in the South Asian population, which is higher than the ClinGen HBOP VCEP threshold (>0.0005) for BS1, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.87, which is above the threshold of 0.733, evidence that correlates with impact to ATM function (PP3). Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets the criteria to be classified as benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BS1, BP2_strong, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA286788/MONDO:0700270/020
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: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.2932T>C | p.Ser978Pro | missense_variant | Exon 20 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | c.2932T>C | p.Ser978Pro | missense_variant | Exon 20 of 63 | NM_000051.4 | ENSP00000501606.1 |
Frequencies
GnomAD3 genomes 0.000440 AC: 67AN: 152138Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000951 AC: 239AN: 251278 AF XY: 0.00124 show subpopulations
GnomAD4 exome AF: 0.000844 AC: 1234AN: 1461714Hom.: 7 Cov.: 36 AF XY: 0.000945 AC XY: 687AN XY: 727166 show subpopulations
Age Distribution
GnomAD4 genome 0.000440 AC: 67AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74454 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:5
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ATM: BS2 -
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Ataxia-telangiectasia syndrome Uncertain:2Benign:5
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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. -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not specified Uncertain:1Benign:4
Classification criteria: BS1_strong, PP3_supporting -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: ATM c.2932T>C (p.Ser978Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 266408 control chromosomes, predominantly at a frequency of 0.0049 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Furthermore, it has also been reported among five individuals who are cancer free at age 70 in the FLOSSIES database. This variant has been reported in multiple affected individuals with classical AT, classical Hodgkins lymphoma, B-NHL, BrC, CRC etc. Among them the one patient with classical AT also carried another ATM variant c.8395-8404del10, and no residual ATM activity was detected via western blot in this patient sample and only about 10% expressed ATM protein detected compared to WT (Carney_2012). However, the possibility of an undetected second variant causing AT in this patient cannot be ruled out. A study evaluating the Rate Ratio of asynchronous contralateral breast cancer associated with ATM gene mutation carrier status found a non-statistically significant risk of contralateral breast cancer for missense variants in the ATM gene (RR 1.2, 95% CI = 0.8 to 1.7) (Bernstein_2010). This low RR and a 95% CI overlapping 1.0 indicate very little confidence in the assertion of association with breast cancer. Subsequently, this variant has been reported in cases and in controls by other studies (example, Dorling_2021). Multiple ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4), likely benign (n=4) and benign (n=5). Based on the evidence outlined above, and the emerging peer consensus, the variant was classified as benign. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
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PP3, BS1, BP2_Moderate c.2932T>C, located in exon 20 of the ATM gene, is predicted to result in the substitution of Ser by Pro at codon 978, p.(Ser978Pro). The variant allele was found in 151/30520 alleles (and 2 homozygotes), with a filter allele frequency of 0.43% at 95% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BS1, BP2_Moderate). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.874) suggests a deleterious effect on protein function (PP3). This variant has been reported in an AT patient in co-ocurrence with a truncating ATM germline mutation, c.8395_8404del; p.(Phe2799Lysfs*4), but the phase of the variants were unknown (PMID: 22649200). This variant has been reported in the ClinVar (10x benign, 10x likely benign, 9x uncertain significance) and in the LOVD database (1x benign, 2x likely benign, 6x uncertain significance). Based on currently available information, the variant c.2932T>C should be considered a likely benign variant. -
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This alteration is classified as 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. -
Breast and/or ovarian cancer Benign:1
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ATM-related cancer predisposition Benign:1
The c.2932T>C variant in ATM is a missense variant predicted to cause substitution of serine by proline at amino acid 978 (p.Ser978Pro). This variant has been observed with the variant c.8395_8404del (p.F2799Kfs*4) which is classified as pathogenic by the HBOP VCEP (ClinVar SCV005627268.1) in one individual with Ataxia-Telangiectasia and 6 individuals with no features of Ataxia-Telangiectasia (PMID: 26896183, Ambry internal data) (PM3/BP2 points: +2). The phase of the variants was suspected to be in cis by family testing. This variant has also been observed with other pathogenic ATM variants in 21 individuals with no features of Ataxia-Telangiectasia (Ambry internal data) (PM3/BP2 points: -42) (BP2_Strong met, -40 points). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004874 in the South Asian population, which is higher than the ClinGen HBOP VCEP threshold (>0.0005) for BS1, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.87, which is above the threshold of 0.733, evidence that correlates with impact to ATM function (PP3). Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. In summary, this variant meets the criteria to be classified as benign for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BS1, BP2_strong, PP3) -
Malignant tumor of breast Benign:1
The ATM p.Ser978Pro variant was identified in 10 of 9598 proband chromosomes (frequency: 0.001) from individuals or families with HBOC, Hereditary Diffuse Gastric Cancer (HDGC), Non-Hodgkin’s lymphoma, Ataxia Telangiectasia (AT), or high risk cancer, and was not identified in 168 control chromosomes from healthy individuals (Yurgelun 2015, Caminsky 2016, Castera 2014, Hansford 2015, Maxwell 2016, Bernstein 2010, Gumy Pause 2006, Carney 2012). The variant co-occurred with an ATM variant (c.8395_8404del) in an AT patient whose residual ATM protein expression level was found to be 10% (Carney 2012). The variant was also identified in dbSNP (ID: rs139552233) “With other allele” and ClinVar (classified as benign by GeneDx, Invitae and Ambry Genetics; as likely benign by EGL Genetic Diagnostics and Counsyl; and as uncertain significance by Praxis fuer Humangentik Tuebingen and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 248 of 277020 chromosomes (2 homozygous) at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 154 (2 homozygous) of 30778 chromosomes (freq: 0.005), Other in 6 of 6456 chromosomes (freq: 0.0009), Latino in 4 of 34408 chromosomes (freq: 0.0001), and European Non-Finnish in 84 of 126608 chromosomes (freq: 0.0007), while it was not observed in the African, Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser978Pro is located in the ß-adaptin binding domain and the p.Ser978 residue is conserved across mammals and other organisms; 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Familial cancer of breast Benign:1
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at