A Spurdle

B Thompson

C Paterson

D Buchanan

D Goldgar

J Hopper

J Young

M Clendenning

M Greenblatt

M Jenkins

M Parsons

M Walsh

null null

R Walters

S Arnold

S Tavtigian

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MEETING ABSTRACT Open Access
Estimation of probabilities in favour of
pathogenicity for missense substitutions for use
in clinical evaluation of mismatch repair gene
variants
B Thompson1*, D Goldgar2, C Paterson1, M Clendenning1, R Walters1, S Arnold1, M Parsons1, M Walsh1,4, J Hopper5
, M Jenkins5,6, M Greenblatt1, Colon Cancer Family Registry, D Buchanan1,4, J Young1, S Tavtigian3, A Spurdle1
From Familial Aspects of Cancer 2011 Research and Practice: A combined meeting of kConFab, Australian
Breast Cancer Family Study, Australian Colorectal Cancer Family Study, Australian Ovarian Cancer Study,
Family Cancer Clinics of Australia and New Zealand and kConFab
Kingscliff, Australia. 23-26 August 2011
A considerable proportion of Lynch syndrome families
present with mismatch repair (MMR) gene sequence var-
iants of uncertain clinical significance, which constitute a
challenge in both the research and clinical settings. Such
unclassified variants (UVs) include rare nucleotide
changes predicted to cause missense substitutions, small
in-frame deletions, or possible alterations in splicing.
We are developing a MMR multifactorial likelihood
model to provide a quantitative measure of MMR var-
iant pathogenicity. Bayes analysis of families to measure
variant causality by segregation methods is established.
Likelihood ratios for microsatellite instability and
somatic BRAF tumour status have also recently been
incorporated into the multifactorial model. We are cur-
rently estimating the prior probability of pathogenicity
for MMR missense substitutions based on the evolution-
ary conservation and physicochemical properties of
amino acid alterations. To this end, we have built and
curated multiple-species sequence alignments of the
four MMR proteins. In parallel, we identified 143 appar-
ent missense substitutions, excluded 12 with evidence of
causing a splice defect, and then used a combination of
quantitative and qualitative criteria to classify 73 as
either pathogenic, likely pathogenic, likely not patho-
genic, or not pathogenic, based on the IARC five-class
system. Six different missense substitution analysis tools
(Align-GVGD, MAPP, MutPred, PolyPhen-2.1, SIFT,
and Xvir) were used to score the missense substitutions.
The bioinformatic outputs are being calibrated by
regression against the classifications of the 73 missense
substitutions to estimate a prior probability of patho-
genicity for MMR missense substitutions.
In summary, we have developed a MMR classification
model including tumour characteristics, segregation ana-
lysis, and in silico prior probability of pathogenicity for
missense substitutions. This multifactorial model will be
applied to the analysis of 34 UVs from Australasian
families, for which we have already completed assess-
ment of tumour pathology, variant association with dis-
ease in families, and bioinformatic and in vitro splicing
analysis. Results from this analysis will alter the manage-
ment of these and other MMR variant-carrying families.
Author details
1Queensland Institute of Medical Research, Brisbane, Australia. 2Department
of Dermatology, University of Utah, Salt Lake City, USA. 3Huntsman Cancer
Institute, University of Utah, Salt Lake City, USA. 4School of Medicine,
University of Queensland, Brisbane, Australia. 5Centre for Genetic
Epidemiology, University of Melbourne, Melbourne, Australia. 6Department of
Medicine, University of Vermont, Burlington, USA.
Published: 12 April 2012
doi:10.1186/1897-4287-10-S2-A31
Cite this article as: Thompson et al.: Estimation of probabilities in favour
of pathogenicity for missense substitutions for use in clinical evaluation
of mismatch repair gene variants. Hereditary Cancer in Clinical Practice
2012 10(Suppl 2):A31.
1Queensland Institute of Medical Research, Brisbane, Australia
Full list of author information is available at the end of the article
Thompson et al. Hereditary Cancer in Clinical Practice 2012, 10(Suppl 2):A31
http://www.hccpjournal.com/content/10/S2/A31
© 2012 Thompson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.


Estimation of probabilities in favour of pathogenicity for missense substitutions for use in clinical evaluation of mismatch repair gene variants

Estimation of probabilities in favour of pathogenicity for missense substitutions for use in clinical evaluation of mismatch repair gene variants

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