11-108249096-T-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.1229T>C(p.Val410Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,613,936 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1229T>C | p.Val410Ala | missense_variant | Exon 9 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00185 AC: 281AN: 152162Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00222 AC: 558AN: 251102Hom.: 2 AF XY: 0.00229 AC XY: 311AN XY: 135716
GnomAD4 exome AF: 0.00292 AC: 4273AN: 1461656Hom.: 9 Cov.: 33 AF XY: 0.00278 AC XY: 2021AN XY: 727132
GnomAD4 genome AF: 0.00185 AC: 281AN: 152280Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:6
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ATM: BS2 -
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Variant summary: The ATM c.1229T>C (p.Val410Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 270/126714 control chromosomes (2 homozygotes) at a frequency of 0.0021308, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this variant is likely a benign polymorphism. This variant has been found in patients with various types of cancer, including breast cancer, uterine serous carcinoma, lymphoma, chronic lymphocytic leukemia, and melanoma. It has not been reported in patients with ataxia-telangiectasia. Two large case-control studies showed that this variant is not associated with breast cancer (Tavtigian 2009; Haiman 2013). Thus available patient and control data show that this variant is a polymorphism found in patients as well as unaffected individuals. In addition, three clinical laboratories have classified this variant as benign/likely benign albeit another lab consider it as uncertain significance, all without evidence to independently evaluate. Taken together, this variant has been classified as Likely benign until more evidence becomes available. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:5
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. -
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Ataxia-telangiectasia syndrome Benign:6
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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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not specified Benign:5Other:1
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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Breast and/or ovarian cancer Benign:1
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Carcinoma of colon Benign:1
The ATM p.Val410Ala variant was identified in 5 of 1492 proband chromosomes (frequency: 0.003) from Dutch and Austrian individuals or families with breast cancer or ovarian cancer, and individuals with pediatric ALL (acute lymphocytic leukemia), and was identified in 2 of 644 chromosomes (frequency: 0.003) from healthy individuals (Broeks_2008_17393301, Thorstenson_2003_12810666, Liberzon_2004_14695997). The variant was also identified as a somatic mutation in 2 studies screening CRCs and lymphomas (Dallol_2016_ 27146902, Fang_2003_12149228). The variant was identified in dbSNP (ID: rs56128736) “With other allele”, ClinVar (wth conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics, GeneDx, and Invitae, likely benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), uncertain significance by Vantari Genetics and Genetic Services Laboratory (University of Chicago), and classification not provided by ITMI), Clinvitae (4x), Cosmic (7x in malignant melanoma, lymphoid neoplasm and carcinoma of the lung), LOVD 3.0, and in control databases in 582 (3 homozygous) of 276862 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 18 of 24018 chromosomes (freq: 0.0007), Other in 14 of 6458 chromosomes (freq: 0.002), Latino in 105 of 34390 chromosomes (freq: 0.003), European Non-Finnish in 401 (2 homozygous) of 126452 chromosomes (freq: 0.003), Ashkenazi Jewish in 41 (1 homozygous) of 10138 chromosomes (freq: 0.004), European Finnish in 3 of 25762 chromosomes (freq: 0.0001), while not observed in the East Asian and South Asian populations. The variant was not identified in GeneInsight-COGR or MutDB. The p.Val410 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Ala to the protein; this information is not very predictive of 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
ATM-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Familial cancer of breast Benign: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]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at