ATM genetic mutation anyone???

Hi BethQ,

I got my genetics panel results today and I have the ATM mutation. I've done some googling and then came to 'my boards' to see if anyone was in the same boat. I have learned to be an active advocate for myself and try to find out everything I can. I have some initial takeaways from my searching that I'm going to share with my 4 sisters. My mom, aunt and great aunt are all early stage survivors and I was diagnosed at age 40 with Stage IV.

What I see cited most often in an increased risk of recurrence with radiation:

http://www.cancer.gov/cancertopics/pdq/genetics/br...

I have also read it has some indications for pancreatic cancer, but can't find the original article now.

I too have the ATM mutation as well as the APC mutation. My geneticist said regarding the ATM mutation that there is not enough studies to correlate the mutation with BC but they have found women who DO have BC and do not carry the BRCA 1/2, TP53, or PTen genes, test positive for the ATM mutation.

He says they are always discovering more info and may someday have more info on that gene.

Here's an interesting article I found that actually confirms my suspicion on the gene. http://www.cancerresearchuk.org/about-cancer/type/breast-cancer/about/risks/breast-cancer-genes

Hello everyone ,I am 62 yrs old, I was diagnosed in Oct. 2014 with my second Breast Cancer, in my left Breast. Stage 1, grade 2, ATM positive,Her2-, Er/pr positive

less than 1cm, large area of insitu.  Lumpectomy, sentinel node biopsy was negative, thank god. I'm waiting for the Onca test results

My first BC was diagnosed 10 yrs ago, in my right breast. A very different cancer. Stage 1, node negative, Her2+, ER positive,PR negative

My older sister was diagnosed 11 yrs ago at age 54

We recently learned that my Aunt on my mothers side died of Breast Cancer @ age 79, because of all of the above they decided to test me for the ATM gene, which both my sister and I tested positive.

I have been reading a lot (of nothing) regarding the ATM gene, too new to have much info.

I called my Genetisis today and asked if she could get in touch with the study going on at Sloan Kettering NYC regarding the ATM gene, findings that woman that had a previous BC, and had radiation are experiencing a new BC in the other breast, just like me.

I'm looking for info regarding the woman they are researching and the average time lapse between cancers.

Anyone out there testing positive for the ATM gene with a second BC in the other breast?

I will post any information I am given.

Hi Gooseylucy,

Sorry you are back. I've found mention of folks with the ATM mutation being sensitive to second cancers possibly caused by radiation. Here are the best articles I've found:

http://www.sciencedaily.com/releases/2010/03/100319202522.htm

http://fortworth.vc.ons.org/file_depot/0-10000000/30000-40000/30106/folder/86165/ATM+Gene+Mutations_May2013.pdf

Hi John:

Regarding the second VUS, you mentioned "Further research said this mutation put women at risk for bilateral breast cancer." This seems to imply the mutation is known to confer increased risk? If true, it would be a deleterious or pathogenic mutation. If so, it would no longer be a VUS and should be reclassified. Has your test provider undertaken to inform you of reclassification? Otherwise, it may simply be that the variant has been seen in some women with bilateral disease (a mere association or presence, such as in your wife), but is still a VUS, and either may or may not confer increased risk (it is not known one way or the other).

Regarding the first VUS, c.1744T>C (p.Phe582Leu) (also referred to as "F582L"), you may want to monitor this NCBI database page about submissions with this change (scroll down to bottom for chart):

http://www.ncbi.nlm.nih.gov/clinvar/variation/1273...

As you poke around, you'll see that different testing services define "VUS" a little differently. Links are provided to documents that describe their classification systems.

Subject to the accuracy and completeness of the database and of the information provided, note that under the supporting observations for a submission from test provider GeneDX, this text appears:

"This variant is denoted ATM c.1744T>C at the cDNA level, p.Phe582Leu (F582L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>CTC) in exon 11. This variant has been reported in association with lymphocytic leukemia and unselected breast cancer (Liberzon 2004, Rudd 2006, Sommer 2002). However, Mitui et al. 2009 reported ATM Phe582Leu as a benign variant exhibiting normal ATM protein levels as well as normal kinase activity and radiosensitivity. ATM Phe582Leu was observed in multiple subpopulations, with the highest allele frequency of 0.2% (4/2100) in 1000 Genomes. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Phe582Leu alters a position that is well conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Phe582Leu is a pathogenic mutation or a benign variant. The variant is found in BR-OV-HEREDIC,HEREDICANCER,PANC-HEREDIC panel(s)."

I googled the citatations plus "ATM gene" to yield the following hits, although I am not sure if they are the exact ones referenced in the quote:

Liberzon 2004: http://onlinelibrary.wiley.com/doi/10.1002/gcc.103...

Rudd 2006: http://www.bloodjournal.org/content/108/2/638.long...

Sommer 2002: http://www.ncbi.nlm.nih.gov/pubmed/11996792

Mitui 2009: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC277673...

BarredOwl

Hi John:

I am not an expert and I am not familiar with the most current literature. I don't know how the second ATM variant, c.146C>G (p.Ser49Cys) is actually classified as of today's date. Patients should first to look to the content of their testing reports, consult with professional genetics counselors, and check back in with their counselors periodically to inquire if the situation has changed. If they do their own research, they should discuss the research findings with a professional to ensure proper interpretation.

Thank you for the link to the 2004 abstract. The full-text paper is also available there.

I take it your wife's test report was issued about 10 yrs later in ~2014 and it classified the variant as a VUS. One need not postulate that a later study negated this 2004 study, if the study did not establish the proposition in the first place. This particular "association study" is not conclusive regarding whether the variant is deleterious or not. The authors state that their results are not consistent with prior studies, and the difference may be due to chance. The authors also state that their "proposal" requires further study to determine "whether this variant may confer an increased risk of breast carcinoma development." This is the text of the Discussion section:

"The novel findings in the current study suggesting a relation between the Ser49Cys variant in ATM and breast carcinoma risk require independent validation. Our case population size was relatively small, and only five case patients had this sequence variant. Nonetheless, the difference in the frequency of this variation in case patients versus control patients was highly significant. The higher frequency of the Ser49Cys variant in women with bilateral breast carcinoma adds support to the proposal that the identity of the variant affects risk.

The Ser49Cys variant has been reported by other authors, although the current report is the first to find this variant more often in case patients than in control patients. Vorechovsky et al.20 were the first to report this variant and considered it to be a rare polymorphism, present in only 1 of 49 breast carcinoma tumors or cell lines. Subsequently, Izatt et al.14 reported this variant in 1 of 100 patients age < 40 years with breast carcinoma, compared with 1 of 50 control patients. Finally, Dörk et al.10 found the Ser49Cys variant in 3 of 192 unselected breast carcinoma cases. It is unclear as to why we found a higher frequency of the Ser49Cys variant in the current patient population compared with previous reports. This discrepancy may be attributable to differences in the study population. For example, Dörk et al. studied a predominantly German population; in addition, the current population had a higher percentage of patients with bilateral breast carcinoma, and the Ser49Cys variant was observed in 11% of this subgroup. Of course, the difference may also be due to chance.

One method for validating the relevance of the Ser49Cys variant to breast carcinoma development would involve testing for this specific variant in a large independent data set. This methodology has been used previously for other genetic variants in ATM.

. . . . In conclusion, we found that a single-base genetic variant in the ATM gene that leads to a Ser49Cys change in the protein product was statistically overrepresented in a breast carcinoma population compared with a control population. These results are useful as hypothesis-generating data that justify further investigation aimed at determining whether this variant may confer an increased risk of breast carcinoma development."

In my layman's view this 2004 paper did not establish that the Ser49Cys variant confers increased risk of breast carcinoma.

BarredOwl

[Edit: An observed association may not establish causation. The final sentence of the discussion of the 2004 paper indicates that as of the date of publication, it was still an open question (whether it may or may not confer increased risk for breast cancer).]

My genetic testing showed ATM mutation and Lynch Syndrome. I'm a cancer time-bomb.

Hi CassieS - I hope this finds you well. I am soon to be 50 and had genetic testing done as I recently lost my mom to ovarian cancer and it was not known if she had a mutation. The test came back with ATM-NM_000051.3 c.7271T>G. I am learning so I see you have this mutation and wanted to reach out. There is so little info. My genetic counselor says my insurance will cover a prophylactic mastectomy and reconstruction. I have appointments scheduled with surgeons for a consult. I have a grandmother who died of pancreatic cancer as did her niece (my dads first cousin). We have prostate and thyroid cancer in that line too. What can you share with me? I have some family that think I'm overreacting. Thanks for any information you have, my guess is you're an ATM expert by now. Maru

Hello - In 2009 my sister died of breast cancer. She was 54. She was 49 when she was diagnosed with invasive ductal carcinoma, stage II with significant lymph node involvement and estrogen positive. She put up a valiant five year fight. My grandmother died from breast and ovarian cancer and my maternal aunt also died from breast cancer at 35. My brother died from pancreatic cancer at 47. I was diagnosed at 35 with thyroid cancer, had surgery and treatment and recovered nicely. After my sister died, my gynecologist (GYN) suggested that I be genetically tested for the breast cancer gene (BRCA 1 & 2). At the time only one lab conducted the testing and it was not a very sophisticated test. To my delight and shock the test came back negative. After my thyroid cancer, I was slammed into early menopause and suffered horribly from hot flashes. The only relief from the hot flashes, and I tried everything, was hormone replacement therapy (HRT). I had been on HRT for about 20 years by this time. Of course this is problematic for someone with my family history. My GYN advised me to start weaning off the HRT, so I did. The hot flashes started to return. The less HRT, the more intense the hot flashes became until I was off the HRT and the hot flashes took over my life. I am not exaggerating. I would have a hot flash 2-3 times an hour. The heat started in the arches of my feet and slowly made its way all the way my body to my head until it felt like my head would explode. It could be 40 degrees outside and I would have to go stand out on our deck to get relief at night. My husband finally had to go sleep in another room because he couldn't sleep with all my up and down. You can only imagine what a zombie I must have been. So, this led me back to my GYN. She really did not want me to go back on HRT but reluctantly agreed if I would agree to be tested again for BRCA 1 & 2. I told her I tested negative, and she said that the testing is so much better now that she just wanted to close the door and if it's still negative, then she saw no reason to use HRT long term. She put me back on meanwhile so I could function until the testing came back. She referred me to a "breast/genetics specialist" who counseled me about how the testing has progressed since 2009, and how it now tests a series of genes and mutations and that although I was negative in 2009, the test was very narrow so we will have to wait and see what the new test shows. So off I went to the lab. About 45 days later, and hot flash free, I get the call from the genetic counselor. She said that the testing showed that I have an ATM Mutation. She explained that my risk of developing breast cancer had increased significantly and that there is a spectrum of other cancers to which I am also at risk: ovarian, thyroid, colon and pancreatic. She asked me if I was shocked by the news. Honestly, I was not all that shocked. I was more shocked back in 2009 when I was negative then now when I was found to be positive. It just seemed so strange to me that with my family history, that I would not have something genetically going on. I went into see her to discuss options. The other risks were not too concerning. I had thyroid cancer which of course now makes perfect sense. At 40, I had a full hysterectomy so ovarian cancer is not a concern. There is testing for colon cancer and my risk of pancreatic cancer is only 5%. The big issue is breast cancer. The risk increased to up over 50% (50%-65%) factoring in family history and all the factors of my sister's diagnosis. UGH those are really horrible odds! I started to do research, read articles, talk to other women, my doctors and my husband. I had two options: do nothing and increase my breast screenings, or proceed with prophylactic surgery. This is a very subjective and personal decision; a decision that has to be made for your own reasons and I chose to proceed with surgery. Let me explain my reasons why. I think the first reason is, I watched my sister fight for her life for five years. She was a wonderful, intelligent, beautiful woman who if she had the same information I had been given, would have jumped at the chance to live. The second reason is, I had already been going through advanced screenings and had been since my sister's death so there really wasn't much more to be done there. The third reason, I really felt like I would have been sitting around waiting for something dreadful to happen and I am not the type of person to sit idle. I am much more proactive than that. The last reason, I felt like I had been given a gift; the gift of information. How often does that happen? I got a glimpse of what the future might hold for me and I got a chance to change that future. Of course, developing breast cancer may never have happened, but why take the chance? I feel like one of the lucky ones. I discussed all of these reasons with my husband and although he agreed with my reasons, his reason was far more practical. He just wanted to make sure that I was around for as long as possible to love him! So on August 9, 2016, I had a bilateral mastectomy with beginnings of reconstructive surgery. Honestly, none of it has been easy, but one year later I have no regrets about the decision that I made. I am in the second phase of my reconstruction and I hope to be finished in 6-9 months. I know that this is a long dissertation, but I wanted to share with any of you who have or just found out that you have an ATM mutation, it is not the end of the world. For me, it was the beginning of new a life. Thanks for listening.