NM_000051.4:c.2494C>T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000051.4(ATM):c.2494C>T(p.Arg832Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R832H) has been classified as Benign.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.2494C>T | p.Arg832Cys | missense_variant | Exon 17 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000296 AC: 45AN: 152030Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000247 AC: 62AN: 251364Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135858
GnomAD4 exome AF: 0.000250 AC: 366AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168AN XY: 727204
GnomAD4 genome 0.000296 AC: 45AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74390
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
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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. -
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not specified Uncertain:1Benign:3
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. -
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Variant summary: ATM c.2494C>T (p.Arg832Cys) 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 0.00023 in 278644 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00023 vs 0.001), allowing no conclusion about variant significance. c.2494C>T has been reported in the literature with varying phenotypes including Lynch syndrome, breast cancer, chronic lymphocytic leukemia, prostate cancer and pancreatic cancer (e.g. Grant_2015, Nadeu_2016, Schwartz_2019, Skowronska_2012, Paulo_2018, Tung_2016, Yurgelun_2015) but also in controls (e.g. Momozawa_2018, Tavtigian_2009). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. A co-occurrence with a pathogenic variant has been reported following internal testing (SMAD4 c.787+2T>C). A ClinVar submitter reports co-occurrence with another mutation in the ATM gene (phase unknown) for the phenotype of Hereditary cancer-predisposing syndrome (SCV000183785.6). Furthermore, the variant was reported in the FLOSSIES database in 5 women older than age 70 years who have never had cancer. Altogether, these data provide supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 140867). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:3
The ATM c.2494C>T; p.Arg832Cys variant (rs2229022; ClinVar ID: 140867) is reported in the literature in individuals affected with breast, pancreatic, or hematological cancers, as well as an individual with suspected Lynch syndrome (Nadeau 2016, Schwartz 2019, Singhal 2021, Tung 2016, Young 2016, Yurgelun 2015). This variant is found in the general population with an overall allele frequency of 0.025% (70/282,748 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.299). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Nadeu F et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016 Apr 28;127(17):2122-30. PMID: 26837699. Schwartz M et al. Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort. Clin Genet. 2019 Dec;96(6):579-584. PMID: 31432501. Singhal D et al. Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer. Leukemia. 2021 Nov;35(11):3245-3256. PMID: 33850299. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8. PMID: 26976419. Young EL et al. Multigene testing of moderate-risk genes: be mindful of the missense. J Med Genet. 2016 Jun;53(6):366-76. PMID: 26787654. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754. -
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Ataxia-telangiectasia syndrome Uncertain:2Benign:1
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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. -
Familial cancer of breast Uncertain:1Benign:1
The ATM c.2494C>T (p.Arg832Cys) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer and pancreatic cancer (PMID: 26976419, 31432501). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
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]. -
Breast and/or ovarian cancer Uncertain:1
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ATM-related disorder Uncertain:1
The ATM c.2494C>T variant is predicted to result in the amino acid substitution p.Arg832Cys. This variant has been reported in individuals with early-onset breast cancer (Table S1, Young et al. 2016. PubMed ID: 26787654; Table A2, Tung et al. 2016. PubMed ID: 26976419), suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), and pancreatic cancer (Table S1, Grant et al. 2015. PubMed ID: 25479140; Schwartz et al. 2019. PubMed ID: 31432501). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/140867/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer Benign:1
This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at