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I'm doing a family study looking for novel cancer-associated variants in germ-line samples; the goal is to find candidate biomarkers which might be used for early detection. At an earlier step our analysis, we eliminated a family that showed a heterozygous mutation known to be associated with our cancer under the premise that this known mutation better explained the presence of the disease than any novel variant we may have found.

I've now found another mutation, strongly associated with out cancer, which we does not appear to be heterozygous. 2 out of 3 family members share this mutation with a within-family allele frequency of 0.5.

Trying to decide whether this means I need to discard this family from further consideration, adjust my thinking, or not worry about it. My current thinking is that it'd be safest to eliminate the family from consideration because the mutation pathogenic and found in the germline but I can't wrap my head around how the lack of a heterozygous pattern affects things. Does it absolutely mean the variant was not inherited? Can anyone help me get my thoughts straight?

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I don't really understand your question. Basically at a given bi-alleleic locus, you have one allele that you suspect to cause cancer. In your sample (not only in one family), this locus in never found in the heterozygous state? And you ask "how is this possible"? Did I understand your question? Have you performed a chi-squared test (or test based on a binomial distribution) in order to test whether the lack of heterozygosity is really unlikely to happen by chance? –  Remi.b Jun 29 at 6:59
    
One of the fundamental premises of this project is that the families we are looking at do not have heritable mutations known to cause cancer (at least not the cancer we're interested in). We eliminated one family from consideration because they showed such a mutation in all members with an allele frequency = 0.5; My question is whether I should eliminate this second family in which 2/3 members have the known, cancer-causing variant for being useless –  Slavatron Jun 30 at 12:52

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