Starting
Initialising…
0%
ATM
Final classification
Likely Benign
ATM c.6572+11C>T · p.?
ATM

NM_000051.4:c.6572+11C>T is an intronic variant located at position +11 in intron 45 of ATM, outside the canonical splice donor site. SpliceAI predicts no splicing impact (max delta score = 0.00), satisfying BP4 (supporting). The variant position at +11 is further than +7 from the donor site, meeting the ATM VCEP definition of a deep intronic variant for BP7 (supporting).

Gene
ATM
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.6572+11C>T
Consequence
N/A
GRCh38
chr11:108321431 C>T
GRCh37
chr11:108192158 C>T
Basis Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting, BP7 supporting; maps to Likely Benign.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
BP4BP7 Likely Benign
ATM c.6572+11C>T

NM_000051.4:c.6572+11C>T is an intronic variant located at position +11 in intron 45 of ATM, outside the canonical splice donor site. SpliceAI predicts no splicing impact (max delta score = 0.00), satisfying BP4 (supporting). The variant position at +11 is further than +7 from the donor site, meeting the ATM VCEP definition of a deep intronic variant for BP7 (supporting).1 This variant is present in gnomAD v4.1 at an allele frequency of 0.00818% (132/1,613,760 alleles; grpmax FAF = 0.0102%) and in gnomAD v2.1 at 0.00495% (14/282,814 alleles). The frequency exceeds the VCEP PM2_Supporting threshold of ≤0.001% but does not reach BS1 (>0.05%) or BA1 (>0.5%) thresholds.2 This variant has been reported in ClinVar as Likely benign by four clinical laboratories and as Benign by one clinical laboratory (ClinVar Variation ID: 490663). While ClinVar consensus favors a benign interpretation, the ATM VCEP does not permit use of BP6, and this evidence is noted for context only.3 No functional studies, case-control data, segregation data, or de novo observations were identified for this variant. PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice sites. PS1 cannot be applied without a PP3 baseline (SpliceAI <0.2).4 Applying the ATM VCEP v1.5.0 ACMG/AMP combination rules: BP4_Supporting and BP7_Supporting are both met (2 benign supporting criteria). Rule 19 (≥2 Benign Supporting) yields a classification of Likely Benign.5

BP4 + BP7 Likely Benign
Gene diagram · NM_000051.4 · variants mapped to exon structure
ATM NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      Population frequency
      Overall AF
      132 / 1,613,760
      0.0082%
      Highest · Admixed American
      0.018%
      Homozygotes
      0
      grpmax FAF
      0.01%
      Allele frequency by ancestry — gnomAD v4.1
      observed in 6 of 9 groups
      AncestryAllele countFrequencyHomozygotes
      Admixed American 11 / 59,982 0.018% 0
      European (non-Finnish) 110 / 1,179,928 0.0093% 0
      African/African American 4 / 74,860 0.0053% 0
      East Asian 2 / 44,882 0.0045% 0
      South Asian 3 / 91,070 0.0033% 0
      European (Finnish) 1 / 63,968 0.0016% 0
      Amish 0 / 912
      Middle Eastern 0 / 6,082
      Ashkenazi Jewish 0 / 29,600
      This variant is present in gnomAD v4.1 (AF= 8.17965e-05; MAF= 0.00818%, 132/1613760 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000183388; MAF= 0.01834%, 11/59982 alleles, homozygotes = 0); grpmax FAF= 0.00010205.
      Overall AF
      14 / 282,814
      0.005%
      Highest · Admixed American
      0.011%
      Homozygotes
      0
      grpmax FAF
      0.0039%
      Allele frequency by ancestry — gnomAD v2.1
      observed in 3 of 8 groups
      AncestryAllele countFrequencyHomozygotes
      Admixed American 4 / 35,440 0.011% 0
      European (non-Finnish) 9 / 129,148 0.007% 0
      African/African American 1 / 24,956 0.004% 0
      Ashkenazi Jewish 0 / 10,370
      East Asian 0 / 19,950
      European (Finnish) 0 / 25,114
      Remaining individuals 0 / 7,220
      South Asian 0 / 30,616
      This variant is present in gnomAD v2.1 (AF= 4.95025e-05; MAF= 0.00495%, 14/282814 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000112867; MAF= 0.01129%, 4/35440 alleles, homozygotes = 0); grpmax FAF= 3.893e-05.
      This variant is absent from gnomAD-Canada.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 490663)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Literature · 22 PMIDs triaged · 8 high-priority
      22papers screened
      Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
      25741868 ↗ functional
      Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
      The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
      BS3PS3PS4
      28779002 ↗ functional
      Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
      Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. Gene coding regions were enriched via PCR, s
      BS3PP5PS3PS4
      34242744 ↗ splicing rna
      Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
      The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the
      BP7PP3PP5PS4PVS1
      15604628 ↗ case observation
      Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
      These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
      PP5PS4
      17508274 ↗ case observation
      Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
      These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
      PP5PS4
      18163131 ↗ case observation
      The emerging landscape of breast cancer susceptibility.
      The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alle
      PP5PS4
      20301317 ↗ case observation
      Untitled reference
      PP5PS4
      20301425 ↗ case observation
      Untitled reference
      PP5PS4
      20050888 ↗ background review
      EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
      PP5PS4
      28492532 ↗ background review
      Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
      PS3PS4
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC