Classifications



Caveat

The information provided on the kConFab website is for research purposes only.

Listed information on classification of gene mutations/variants is subject to change as further information becomes available. It is not intended for clinical use, by clinicians or families. Individuals or families requiring advice should consult their doctor or contact a local Family Cancer Clinic.

Published models have been used to arrive at the classification for some gene mutations/variants. This information should be interpreted bearing in mind that the rarity of variants may limit the data informing the models used. In general, classification methods for familial cancer genes are aimed to distinguish high-risk from no/low risk variants and may not reliably identify variants with intermediate risk effect.

Nomenclature

BRCA1 and BRCA2 variants are described using HGVS and BIC nomenclature. All other gene variants are described using HGVS nomenclature only.

  1. HGVS Nomenclature: nomenclature following HGVS recommendations (http://www.hgvs.org/mutnomen/recs.html).
  2. BIC Nomenclature: nomenclature following HGVS recommendations, but with the following exceptions:
    1. the nucleotide numbering is from nucleotide 1 of the full gene sequence (Genbank: U14680.1/ BRCA1; U43746/ BRCA2) not the ATG initiator codon, as coincides with numbering used by BIC (http://research.nhgri.nih.gov/bic/)
    2. BRCA1 exon boundaries are from GenBank U14680.1, that is, exon 4 is missing due to a correction made after the initial description of the gene.
    3. the BRCA1 185del AG and BRCA1 5382insC pathogenic variants have not been re-named, following universal use of the incorrect base numbers in the literature

Reference sequences are as follows:

ATM. Coding DNA reference sequence based on U82828, from genomic refseq NG 009830.1, covering ATM transcript NM 000051.3. Note: Two ATM transcripts have been reported - one starting in exon 1a (NM_000051.3) and one in exon 1b (located in intron 1).

BRCA1. Coding DNA reference sequence from genomic refseq NG_005905.2 (same as LRG 292) covering BRCA1 transcript NM_007294.3. Exon boundaries from GenBank U14680.1, that is, exon 4 is missing due to a correction made after the initial description of the gene.

BRCA2. Coding DNA reference sequence from genomic refseq NG_012772.3 (same as LRG 293), covering BRCA2 transcript NM_000059.3.

CHEK2. Coding DNA reference sequence from genomic refseq NG_008150.1, covering CHEK2 transcript NM_007194.3.

MLH1. Coding DNA reference sequence from genomic refseq NG_007109.1, covering MLH1 transcript NM_000249.3.

MSH2. Coding DNA reference sequence from genomic refseq NG_007110.1, covering MSH2 transcript NM_000251.1.

MSH6. Coding DNA reference sequence from genomic refseq NG_007111.1, covering MSH6 transcript NM_000179.2.

PALB2/FANCD2. Coding DNA reference sequence from genomic refseq NG_007406.1 (identical to LRG_308), covering FANCD2 transcript NM_024675.3.

PMS2. Coding DNA reference sequence from genomic refseq NG_008466.1, covering PMS2 transcript NM_000535.5.

PTEN. Coding DNA reference sequence from genomic refseq NG_007466.2 (same as LRG 311), covering PTEN transcript NM_000314.4.

TP53. Coding DNA reference sequence from genomic refseq NG_017013.2 (same as LRG 321), covering TP53 transcript NM_000546.5.

Classification of Variants

In determining the classifications for variants observed in kConFab families, a literature review is performed and consideration is given to the classification guidelines listed below, current clinical practice in Australia, and with cross-reference to variant databases for cancer predisposition genes.

Unless otherwise specified, variants are assigned a class according to a 5 tier clinical classification scheme that assumes high cancer risk for variants leading to abrogated protein function, following recommendations of Plon et al (2008, Hum Mutat, 29, 1282-91), and adaptations for qualitative classification introduced by InSiGHT (http://insight-group.org/variants/classifications/) and ENIGMA (http://www.enigmaconsortium.org/).


Class Quantitative Measure: Probability of Pathogenicity Qualitative Measure: Rules-based interpretation of data – examples Predictive Testing of At-Risk Relatives Surveillance for At-Risk Relativesa Research Testing of Relatives
5: Pathogenic >0.99 Variant sequence encoding a truncated protein; Variant leading to aberrant mRNA transcript encoding a truncated protein Yes Full high-risk guidelines for variant carriers Not indicated
4: Likely pathogenic 0.95-0.99 Variant at canonical splice site, untested for splicing Yesb Full high-risk guidelines for variant carriers Yes
3: Uncertain 0.05-0.949 Uncertain; Insufficient information Nob Based on family history & other risk factors Yes
2: Likely not pathogenic or of little clinical significance 0.001-0.049 Encodes same amino acid change as non-pathogenic AND no evidence of mRNA aberration Nob Based on family history & other risk factors - treat as “no BRCA1/2 pathogenic variant detected” for this disorder Yes
1: Not pathogenic or of little clinical significance <0.001 Common variant in non-founder population Nob Based on family history & other risk factors - treat as “no BRCA1/2 pathogenic variant detected” for this disorder Not indicated
aAdapted for clarity from original tabular presentation published in (Plon et al, 2008, Hum Mutat, 29, 1282-91.
bRecommend continued testing of proband for any additional available testing modalities available e.g. large genomic rearrangements.

Variants are assessed by designated committee members or affiliates as follows:

  • BRCA1/2 – according to ENIGMA BRCA classification criteria (http://www.enigmaconsortium.org/)
  • MMR – according to the InSiGHT classification criteria for MMR genes (http://insight-group.org/variants/classifications/)
  • PALB2 – according to classification criteria developed by the kConFab variant review committee (link to PALB2 doc)
  • TP53 – according to clinical genetic test reporting standards
  • PTEN – according to clinical genetic test reporting standards
  • ATM – according to research-derived risk estimates, with report-back according to recommendations of eviQ (https://www.eviq.org.au/) and/or approval of FCC heads.
  • CHEK2 – according to research-derived risk estimates, with report-back according to recommendations of eviQ (https://www.eviq.org.au/) and/or approval of FCC heads

Note - criteria used for historical kConFab classifications are detailed here