Genetic testing--hot health history

You may qualify for BRCA testing especially if you are young. When I had mine done it took 1 month to get results but perhaps they have sped things up a bit. Good luck with your MRI and I hope your nodes are clear.

poodles - Sorry about the disconcerting news. How crazy is it to have both mutations? Iguess it good to know about it. My DDIL's mom is BRCA1 pos but DDIL is neg. it was good to have that info. Please let us know what your GC says. I had a Bmx and have never regretted it. It is what it is. Hugs!

Hi mustlovepoodles:

Sorry to hear you have not one, but two mutations (PALB2 and CHEK2).

Did the counselor tell you if the mutations are: (a) a deleterious or pathogenic mutation, (b) a polymorphism, or (c) a variant of unknown significance?

Also, PALB2 (chromosome 16) and CHEK2 (chromosome 22) appear to be on different chromosomes. You have two copies of each chromosome, and an egg has one copy of each chromosome. So the risk of you passing one of these genes on to a child is 50%. When both genes are considered, it seems to me that the combined risk of a child receiving either or both can be higher.

This situation is analogous to the situation of a person who had both a BRCA1 and a BRCA2 mutation (also on different chromosomes). This seems to be called "double heterozygosity" ("DH"). One article I found seems to suggest that the risk of passing a mutated gene on to a child is up to 75% with "DH":

"The main difference in counselling [sic] between carriers of a single mutation and people with DH lies in the risks for first degree relatives and other family members. These are confronted with a risk of carrying a mutation up to 75%. . . "

As I understand it, any one child could theoretically have received from you: (a) neither mutation, (b) only the PALB2 mutation, (c) only the CHEK2 mutation, or (d) both PALB2 and CHEK2 mutations. That comes out to a 25% chance of receiving no mutation, and a 75% chance of receiving either one or both mutations from you.

I am a only layperson, and I may be completely wrong. I raised this question in another thread re BRCA1/BRCA2, where the moderators had initially said the risk was 50%, and in response, the moderators edited their post to indicate the risk from carrying two mutations (on different chromosomes) would be higher than 50%. Here is the thread:

https://community.breastcancer.org/forum/112/topic...

The moderators are not genetic specialists either, so I think this is a question you may wish to revisit with your genetic counselor, or optionally, which your children can investigate if they seek counseling. Of course, if the risk of having a mutation for each of your children actually was higher than 50%, that could influence their decision to seek counseling in the first place.

By the way, you and your mom should keep in mind the wonderful traits you have passed on.

BarredOwl

Hi mustlovepoodles:

You didn't oversimplify at all. I asked about the kind of genetic change, because variants of unknown significance can be confusing.

You may realize this already and sorry if I am stating the obvious, but my post above relates to the chance of passing a mutation to a child: this chance (which I think may be as high as 75% when two genes are involved, and is subject to confirmation with your genetic counselor) is totally independent of the estimated lifetime risk of certain cancers once a child has received one or both genes. And hopefully, they got neither.

PALB2: The estimate of lifetime risk from having a "pathogenic" mutation in PALB2 that you got may come from this recent study. The study looked at a number of different mutations found in various families, and reports a composite range of 33 % - 58% breast cancer risk by 70 yrs of age, and there are some refinements noted:

"The cumulative risk estimates for female PALB2 mutation carriers, calculated with the use of different assumptions about family history of breast cancer, are shown in Table 4. By 70 years of age, breast-cancer risk ranged from 33% (95% CI, 25 to 44) for a female carrier with no affected relatives to 58% (95% CI, 50 to 66) for a female carrier with two first-degree relatives who had breast cancer diagnosed by 50 years of age. Such differences in risk are consistent with previous observations, and it is possible that family history and PALB2 genotype should be considered together in determining the risk level and appropriate management."

The above quote is from the second paragraph of the Discussion, and the full text article for information only is here (for info only):

http://www.nejm.org/doi/full/10.1056/NEJMoa1400382...

It looks like less is known about the particular CHEK2 mutation you have, but screening is available for both types of cancers they listed, which is something.

You may want to stay in touch with your genetic counselor over the years. As more research accumulates, and guidelines evolve, they may be able to provide you with more concrete advice.

BarredOwl

Hi mustlovepoodles:

It sounds like you have given this a lot of careful thought and you have a good plan. Your daughter and other family members have time to learn, seek professional advice, and think things over carefully before coming to a personal decision that is right for them.

BarredOwl

Hi ChiSandy:

I remember the long wait for BRCA results, which luckily came in negative in my case. I have chosen not to have any further testing for now.

Your oncologist is not so out there. In this regard, you might be interested in this article by Dr. Mary Claire King discussing a study of population-based screening in an Ashkenazi Jewish population in Israel.

http://jama.jamanetwork.com/article.aspx?articleid...

This study looked for specific mutations. As noted, there may be differences between populations in Israel and the U.S.

I am not sure if you are having BRCA only testing or a multi-gene panel test. Regarding multi-gene panel testing, I found this article which observed less of an age effect for genes other than BRCA to be quite interesting:

http://oncology.jamanetwork.com/article.aspx?artic...

The trial "prospectively enrolled 1046 individuals who were appropriate candidates for HBOC [hereditary breast and ovarian cancer] evaluation and who lacked BRCA1/2 mutations." Among these, "The vast majority were women, and 83% had a personal history of breast and/or ovarian carcinoma, while only 14% were cancer unaffected. . ." "An additional 23 patients referred to our centers and harboring non-BRCA1/2 mutations were enrolled and included in subsequent analyses."

They "carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals." The multigene panels used were: "the 29-gene Hereditary Cancer Syndromes test (Invitae), used at Stanford and MGH, or the 25-gene MyRisk test (Myriad Genetics), used at BIDMC." [MGH, Mass General Hospital and BIDMC, Beth Israel Deaconess Medical Center]

Mutations in other genes were not that common: "Consistent with recently reported findings from other similar cohorts (15, 17-19) and our group's published work (10,16,20), we found that 3.8% of BRCA1/2mutation-negative individuals (95% CI, 2.8%-5.2%) harbored deleterious mutations in other hereditary cancer predisposition genes."

However, among the group of mutation carriers, the following findings are interest (emphasis added by me):

• "A substantial subset of individuals (20 of 63) were found to have mutations in high-risk genes associated with detailed NCCN consensus management guidelines, and in these instances finding the mutation would always change management (Table 2). Notably, although these individuals had personal and/or family histories consistent with the mutation, many would not have met established gene and/or syndrome-specific testing criteria. Thus, these clinically significant mutations may have been missed by the traditional, focused testing approach. The potential clinical effect of finding these mutations was equally important for patients' family members: testing of additional family members would be recommended in all cases (Table 1). (1, 22)"

• "Notably, among patients with breast cancer, we did not observe an effect of age at diagnosis on the prevalence of breast cancer–associated genes (Figure 1). This situation is quite different from BRCA1/2, the prevalence of which is strongly age dependent, and suggests that diagnosis age is not a reliable indicator of mutation probability when testing for these other genes."

The article is well-written and organized (with supplemental material under tabs at top), and I think it provides some good information for those considering multigene panel testing or who wish to learn more about it.

By the way, I am not advocating multi-gene panel testing for anyone. At the same time, I would not question the decision of anyone who has chosen such testing for themselves. There are some down-sides for "worriers" like me, including the lack of consensus practice guidelines for deleterious mutations in many genes, the absence of effective screening and/or risk management options for some associated cancers, variants of unknown significance, and the inclusion of some genes that are almost totally uncharacterized in terms of the level of risk.

Best wishes to you for clearly negative results!

BarredOwl

Night: Just read your posts and am wishing you the best. I ended up having multi-gene panel test, at recommendation of my onc (due to family history), and came back negative for BRCA and all other BC-related mutations. Got a single "variant of unknown significance" result for a gene associated with colorectal cancer (for which I have no family history, and I am screened regularly).

Waiting for the results was enormously stressful for me. And definitely have family predisposition going on...it's just not something identifiable. So I will be vigilant, live healthy, and be glad it's not BRCA. Thinking of you!

must love poodles. Sorry you have to be here but welcome. Just want to let you know you have listed your hormone receptors different in your diagnosis than your pathology report. I assume your path report is the correct one right? Considering your family history it was fortunate you caught it in the early stages. The treatment plan sounds right on the money. Good luck and keep us posted.....