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Any recent reported cancer cases of PMS2 gene p.E635k?
Are there any recent reported ovarian cancer cases caused by PMS2 gene p.E635k? Two sisters recently died of ovarian cancer with this same gene variant of unknown significance. I wondered if there were other cases? Obviously not enough cases to warrant a cluster but I wanted to find out if data is kept on genetic variants of unknown significance to establish a significant cause. The family on either side have no medical history of cancer. We were (3 younger sisters and 5 brothers) raised on a farm northeast of Rochester where our father was a heavy user of herbicides in the 1960's. My two deceased sisters were in their teens at that time. Thank you for any assistance.
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I just tried looking this gene variant up, and it appears to be very rare. I looked at this part of PMS2 in the gnomAD database, which lists all reported germline variants from the various human genome sequencing projects, and p.E635K isn't there. Unless your family is from an isolated population that isn't well-represented in the sequencing projects, this probably means that this variant is extremely rare, possibly unique to your extended family. So it's going to be hard to figure out if this variant increases cancer risk.
One thing you might try to find out is whether your sisters' cancers showed a mismatch repair (MMR) defect, which they should if PMS2 is defective. Often this is done by immunohistochemistry for the Mlh1, Msh2, Msh6, and Pms2 proteins. But in this case it would be better if they tested for microsatellite instability (MSI) in the DNA, to see if MMR was functional, not just whether the proteins were there. If your sisters' cancers were NOT defective in MMR, then the PMS2 variant probably had nothing to do with the cancer. Hopefully they did these tests while your sisters were alive. If they did a sequencing test like Caris, this would be included. But if not, you might be able to convince the genetic counselor to do them on the archived tumor tissue. I assume you're worrying about other family members who might also carry this variant.